Oxazolyl-aryloxyacetic acid derivatives and their use as ppar agonists

ABSTRACT

Compounds represented by the following structural formula (I), and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein R1 is an unsubstituted or substituted aryl, heteroaryl, cycloalkyl, aryl-alkyl, heteroaryl-alkyl or cycloalkyl-alkyl, R2 is H, alkyl or haloalkyl, the polymethylene chain (II), is saturated or may contain a carbon-carbon double bond, while n is 2, 3, 4, W is O or S, Y is an unsubstituted or substituted phenylene, naphthylene or 1, 2, 3, 4 tetrahydronaphthylene, R3 is H, alkyl or haloalkyl, R4 is H, alkyl, haloalkyl or a substituted or unsubstituted benzyl, are useful for modulating a preoxisome proliferator activated receptor, particularly in the treatment of diabetes mellitus.

BACKGROUND OF THE INVENTION

Peroxisome Proliferator Activated Receptors (PPARs) are members of thenuclear hormone receptor super family, which are ligand-activatedtranscription factors regulating gene expression. Various subtypes ofPPARs have been discovered. These include PPARα, PPARγ and PPARδ.

The PPARα receptor subtypes are reported to be activated by medium andlong-chain fatty acids. They are involved in stimulating beta-oxidationof fatty acids and with the activity of fibrates which reportedlyproduce a substantial reduction in plasma triglycerides and moderatereduction in low density lipoprotein (LDL) cholesterol. The PPARγreceptor subtypes are reportedly involved in activating the program ofadipocyte differentiation and are not involved in stimulating peroxisomeproliferation in the liver.

Diabetes is a disease in which a mammal's ability to regulate glucoselevels in the blood is impaired because the mammal has a reduced abilityto convert glucose to glycogen for storage in muscle and liver cells. InType I diabetes, this reduced ability to store glucose is caused byreduced insulin production. “Type II Diabetes” or “non-insulin dependentdiabetes mellitus” (NIDDM) is the form of diabetes which is due to aprofound resistance to insulin stimulating or regulatory effect onglucose and lipid metabolism in the main insulin-sensitive tissues,muscle, liver and adipose tissue. This resistance to insulinresponsiveness results in insufficient insulin activation of glucoseuptake, oxidation and storage in muscle and inadequate insulinrepression of lipolysis in adipose tissue and of glucose production andsecretion in liver. When these cells become desensitized to insulin, thebody tries to compensate by producing abnormally high levels of insulinand hyperinsulemia results. Hyperinsulemia is associated withhypertension and elevated body weight. Since insulin is involved inpromoting the cellular uptake of glucose, amino acids and triglyceridesfrom the blood by insulin sensitive cells, insulin insensitivity canresult in elevated levels of triglycerides and LDL which are riskfactors in cardiovascular diseases. The constellation of symptoms whichincludes hyperinsulemia combined with hypertension, elevated bodyweight, elevated triglycerides and elevated LDL is known as Syndrome X.

Current treatment for diabetes mellitus generally first involvestreatment with diet and exercise. However, compliance can be poor and asthe disease progresses treatment with hypoglycemics, typicallysulfonylureas, is often necessary. Sulfonylureas stimulate the β cellsof the liver to secrete more insulin. However, the response of the βcells eventually fails and treatment with insulin injection isnecessary. In addition, both sulfonylurea treatment and insulininjection have the life threatening side effect of hypoglycemic coma.Therefore, patients using these treatments must carefully controldosage.

Thiazolidinediones are a class of compounds which have been shown toincrease the sensitivity of insulin sensitive cells. Increasing insulinsensitivity rather than the amount of insulin in the blood reduces thelikelihood of hypoglycemic coma. Thiazolidinediones have been shown toincrease insulin sensitivity by binding to PPARγ receptors. However,side effects associated with treatment with thiazolidinediones includeweight gain, and, for troglitazone, liver toxicity.

PPARα and PPARγ receptors have been implicated in diabetes mellitus,cardiovascular disease, obesity, and gastrointestinal disease, such as,inflammatory bowel disease. There exists a need for new pharmaceuticalagents which modulate these receptors to prevent, treat and/or alleviatethese diseases or conditions while ameliorating side effects of currenttreatments.

SUMMARY OF THE INVENTION

The present invention is directed to compounds represented by StructuralFormula I and pharmaceutically acceptable salts, solvates and hydratesthereof:

In Structural Formula I, R1 is an unsubstituted or substituted groupselected from aryl, heteroaryl, cycloalkyl, aryl-C1-C4 alkyl,heteroaryl-C1-C4 alkyl or cycloalkyl-C1-C4 alkyl. R2 is H, C1-C4 alkylor C1-C4 haloalkyl. The polymethylene chain,

is saturated or may contain a carbon-carbon double bond, while n is 2,3, or 4. W is O or S. Y is an unsubstituted or substituted groupselected from phenylene, naphthylene or 1,2,3,4 tetrahydronaphthylene.R3 is H, C1-C6 alkyl or C1-C6 haloalkyl. R4 is H, C1-C10 alkyl, C1-C10haloalkyl, or a substituted or unsubstituted benzyl. However, when R3and R4 are H, R2 is C1-C4 alkyl or C1-C4 haloalkyl. R5 is H, C1-C4 alkylor aminoalkyl.

In one embodiment, the present invention also relates to pharmaceuticalcompositions which comprising at least one compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, hydrate orprodrug thereof, and a pharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a method ofmodulating a peroxisome proliferator activated receptor by contactingthe receptor with at least one compound represented by StructuralFormula I, and pharmaceutically acceptable salts, solvates and hydratesthereof.

In a further embodiment, the present invention relates to a method ofmaking a compound represented by Structural Formula I.

The compounds of the present invention and pharmaceutically acceptablesalts, solvates and hydrates thereof are believed to be effective intreating Syndrome X, Type II diabetes, hyperglycemia, hyperlipidemia,obesity, coagaulopathy, hypertension, atherosclerosis, and otherdisorders related to Syndrome X and cardiovascular diseases because theylower one or more of the following in mammals: glucose, insulin,triglycerides, fatty acids and/or cholesterol. In addition, thecompounds exhibit fewer side effects than compounds currently used totreat these conditions.

DETAILED DESCRIPTION OF THE INVENTION

The terms used to describe the instant invention have the followingmeanings herein.

As used herein, alkyl groups include straight chained or branched C1-C6hydrocarbons, which are saturated or unsaturated.

Cycloalkyl groups, as used herein, include C3-C8 hydrocarbons, which arepartially or completely saturated.

As used herein, aryl groups include carbocyclic aromatic ring systems(e.g. phenyl), fused polycyclic aromatic ring systems (e.g. naphthyl andanthracenyl) and aromatic ring systems fused to carbocyclic non-aromaticring systems (e.g., 1,2,3,4-tetrahydronaphthyl).

Heteroaryl groups, as used herein, is an aromatic ring system having atleast one heteroatom such as nitrogen, sulfur or oxygen. Heteroarylgroups include thienyl (also referred to herein as “thiophenyl”),pyridyl, pyrrolyl, benzofuranyl, isoxazolyl, and pyrimidinyl.

An aryl-C1-C4-alkyl group, as used herein, is an aryl substituent thatis linked to a compound by a saturated or unsaturated alkyl group havingfrom one to our carbon atoms.

A heteroaryl-C1-C4-alkyl group, as used herein, is a heteroarylsubstituent that is linked to a compound by a saturated or unsaturatedalkyl group having from one to four carbon atoms.

A cycloalkyl-C1-C4-alkyl group, as used herein, is a cycloalkylsubstituent that is linked to a compound by a saturated or unsaturatedalkyl group having from one to four carbon atoms.

An aminoalkyl group is an alkyl group having from one to six carbonatoms which is substituted with at least one amine represented by—NR12R12 in which each R12 are, independently, a C1-C6 alkyl or both R12taken together with the nitrogen to which they are attached form a fiveor six membered heterocycloalkyl.

A heterocycloalkyl is a non-aromatic ring which contains one or moreoxygen, nitrogen or sulfer (e.g., morpholine, piperidine, piperazine,pyrrolidine, and thiomorpholine). The preferred heterocycloalkyl groupis morpholine.

Substituents for aryl, heteroaryl and cycloalkyl groups include halo,hydroxy, carboxy, saturated or unsaturated C1-C4 alkyl, C1-C4 alkoxy,C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano, carbamoyl, dioxaborolan-2-yl,benzoyl, or a substituted or unsubstituted group selected fromaryl-C1-C4-alkyl, aryloxy, cycloalkyl, cycloalkyloxy or heterocyclo-oxy.Substituents for heteroaryl groups further include biphenyl. Preferredsubstituents for aryl are independently selected from CF₃, carboxy,saturated or unsaturated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,C1-C4 haloalkoxy, cyano, carbamoyl, dioxaborolan-2-yl, benzoyl, or asubstituted or unsubstituted group selected from aryl-C1-C4-alkyl,aryloxy, cycloalkyl, cycloalkyloxy or heterocyclo-oxy.

Substituents for the phenylene, naphthylene or 1,2,3,4tetrahydronaphthylene groups include halo, C1-C6 alkyl, C1-C6 alkoxy,C1-C6 haloalkyl, C1-C6 haloalkoxy, cycloalkyl-C1-C4 alkyl, or aryl-C1-C4alkyl.

Preferably, the compounds of the present invention, and with theirrespective pharmaceutical compositions, have a structure represented byStructural Formula II:

In Structural Formula II and IIa, R1 and R5 are as defined forStructural Formula I. R6 are each, independently, H, halo, C1-C6 alkyl,C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cycloalkyl,cycloalkyl-C1-C4 alkyl, aryl-C1-C4 alkyl, or together with the phenyl towhich they are bound form naphthyl or 1,2,3,4-tetrahydronaphthy. R7 areeach, independently, H, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6haloalkyl, C1-C6 haloalkoxy, cycloalkyl-C1-C4 alkyl, or aryl-C1-C4 alkylor C1-C6 alkoxybenzyl, C1-C6 alkoxyaryl or a group of the formula

R8 is C1-C4 alkyl or C1-C4 haloalkyl. R9 is C1-C6 alkyl or C1-C6haloalkyl. R10 is C1-C10 alkyl, C1-C10 haloalkyl, or a substituted orunsubstituted benzyl. R13 is selected from the group consisting ofbenzyl, substituted benzyl, C1-C6 cycloalkyl, C1-C6 alkyl.

Substituents for benzyl include, for example, C1-C4 alkyl, C1-C4alkyloxy, C1-C4 haloalkyl, C1-C4 haloalkoxy or phenyl.

Examples of compounds having Structural Formula II include, forinstance, the compounds described in Examples 1-2, 6-7, 9-32, 37-39HHand Examples 45, 46, 48-63. Examples of compounds having structuralFormula IIa include, for instance, the compounds described in Examples40, 41, 42, 43, 44 and 47.

More preferably, the compounds of the present invention, and with theirrespective pharmaceutical compositions, have a structure represented byStructural Formula III:

In Structural Formula III, R5, R6, R7 and RID are as defined forStructural Formulas I and II while. R11 is halo, hydroxy, carboxy,saturated or unsaturated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,C1-C4 haloalkoxy, cyano, carbamoyl, dioxaborolan-2-yl, benzoyl, or asubstituted or unsubstituted group selected from aryl-C1-C4-alkyl,aryloxy, cycloalkyl, cycloalkyloxy or heterocyclo-oxy.

In another preferred embodiment, the compounds of the present invention,and with their respective pharmaceutical compositions, have a structurerepresented by Structural Formula IV:

In Structural Formula IV, R5, R6, R7 and R10 are as defined forStructural Formulas I and II while R12, which is a substituent at the 1,2, 3 or 4 carbon position of the cyclohexyl, is H, aryl or C1-C4 alkyl.

The compounds of Structural Formula I may contain one or more chiralcenters, and exist in different optically active forms. When compoundsof Structural Formula I contain one chiral center, the compounds existin two enantiomeric forms and the present invention includes bothenantiomers and mixtures of enantiomers, such as racemic mixtures. Theenantiomers may be resolved by methods known to those skilled in theart, for example by formation of diastereoisomeric salts which may beseparated, for example, by crystallization; formation ofdiastereoisomeric derivatives or complexes which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic esterification; or gas-liquid or liquidchromatography in a chiral environment, for example on a chiral supportfor example silica with a bound chiral ligand or in the presence of achiral solvent. It will be appreciated that where the desired enantiomeris converted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

When a compound represented by Structural Formula I has more than onechiral substituent it may exist in diastereoisomeric forms. Thediastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. The present invention includes each diastereoisomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in zwitterionic formand the present invention includes each zwitterionic form of compoundsof Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I and their salts may exist inmore than one crystal form. Polymorphs of compounds represented byStructural Formula I form part of this invention and may be prepared bycrystallization of a compound of Structural Formula I under differentconditions. For example, using different solvents or different solventmixtures for recrystallization; crystallization at differenttemperatures; various modes of cooling, ranging from very fast to veryslow cooling during crystallization. Polymorphs may also be obtained byheating or melting a compound of Structural Formula I followed bygradual or fast cooling. The presence of polymorphs may be determined bysolid probe nmr spectroscopy, ir spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

Certain compounds of Structural Formula I and their salts may exist inmore than one crystal form and the present invention includes eachcrystal form and mixtures thereof.

Certain compounds of Structural Formula I and their salts may also existin the form of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

“Pharmaceutically-acceptable salt” refers to salts of the compounds ofthe Structural Formula I which are substantially non-toxic to mammals.Typical pharmaceutically-acceptable salts include those salts preparedby reaction of the compounds of the present invention with a mineral ororganic acid or an organic or inorganic base. Such salts are known asbase addition salts, respectively. It should be recognized that theparticular counterion forming a part of any salt of this invention isnot of a critical nature, so long as the salt as a whole ispharmaceutically-acceptable and as long as the counterion does notcontribute undesired qualities to the salt as a whole.

By virtue of its acidic moiety, a compound of Structural Formula I formssalts with pharmaceutically acceptable bases. Some examples of baseaddition salts include metal salts such as aluminum; alkali metal saltssuch as lithium, sodium or potassium; and alkaline earth metal saltssuch as calcium, magnesium, ammonium, or substituted ammonium salts.Examples of substituted ammonium salts include, for instance, those withlower alkylamines such as trimethylamine, triethylamine;hydroxyalkylamines such as 2-hydroxyethylamine,bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine,cycloalkylamines such as bicyclohexylamine or dibenzylpiperidine,N-benzyl-β-phenethylamine, dehydroabietylamine,N,N′-bisdehydro-abietylamine, glucamine, N-methylglucamine; bases of thepyridine type such as pyridine, collidine, quinine or quinoline; andsalts of basic amino acids such as lysine and arginine.

Examples of inorganic bases include, without limitation, sodiumhydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like.

Compounds of Structural Formula I, which are substituted with a basicgroup, may exist as salts with pharmaceutically acceptable acids. Thepresent invention includes such salts. Examples of such salts includehydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, tartrates [e.g. (+)-tartrates,(−)-tartrates or mixtures thereof including racemic mixtures],succinates, benzoates and salts with amino acids such as glutamic acid.

These salts may be prepared by methods known to those skilled in theart.

Certain compounds of Structural Formula I and their salts may also existin the form of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

Prodrugs are compounds of the present invention, which have chemicallyor metabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention which arepharmaceutically active in vivo. Prodrugs include acid derivatives wellknown to practitioners of the art, such as, for example, esters preparedby reaction of the parent acidic compound with a suitable alcohol, oramides prepared by reaction of the parent acid compound with a suitableamine. Simple aliphatic or aromatic esters derived from acidic groupspendent on the compounds of this invention are preferred prodrugs. Insome cases it is desirable to prepare double ester type prodrugs such as(acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularlypreferred esters as prodrugs are methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tert-butyl, morpholinoethyl, andN,N-diethylglycolamido.

Methyl ester prodrugs may be prepared by reaction of the acid form of acompound of Formula I in a medium such as methanol with an acid or baseesterification catalyst (e.g., NaOH, H₂SO₄). Ethyl ester prodrugs areprepared in similar fashion using ethanol in place of methanol.Morpholinylethyl ester prodrugs may be prepared by reaction of thesodium salt of a compound of Structural Formula I (in a medium such asdimethylformamide) 4-(2-chloroethyl)morphine hydrochloride (availablefrom Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).

The term, “active ingredient” means the compounds generically describedby Structural Formula I as well as the salts, solvates, and prodrugs ofsuch compounds.

The term “pharmaceutically acceptable” means that the carrier, diluent,excipients and salt must be compatible with the other ingredients of thecomposition, and not deleterious to the recipient thereof.Pharmaceutical compositions of the present invention are prepared byprocedures known in the art using well known and readily availableingredients.

“Preventing” refers to reducing the likelihood that the recipient willincur or develop any of the pathological conditions described herein.

“Treating” refers to mediating a disease or condition and preventing, ormitigating, its further progression or ameliorate the symptomsassociated with the disease or condition.

“Pharmaceutically-effective amount” means that amount of a compound, orof its salt, solvate, hydrate or prodrug thereof, that will elicit thebiological or medical response of a tissue, system, or mammal. Such anamount can be administered prophylactically to a patient thought to besusceptible to development of a disease or condition. Such amount whenadministered prophylactically to a patient can also be effective toprevent or lessen the severity of the mediated condition. Such an amountis intended to include an amount which is sufficient to modulate a PPARreceptor, such as a PPARα or PPARγ receptor, which mediate a disease orcondition. Conditions mediated by PPARα or PPARγ receptors includediabetes mellitus, cardiovascular disease, Syndrome X, obesity andgastrointestinal disease.

A “mammal” is an individual animal that is a member of the taxonomicclass Mammalia. The class Mammalia includes humans, monkeys,chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice,and rats.

Administration to a human is most preferred. The human to whom thecompounds and compositions of the present invention are administered hasa disease or condition in which control blood glucose levels are notadequately controlled without medical intervention, but wherein there isendogenous insulin present in the human's blood. Non-insulin dependentdiabetes mellitus (NIDDM) is a chronic disease or conditioncharacterized by the presence of insulin in the blood, even at levelsabove normal, but resistance or lack of sensitivity to insulin action atthe tissues. The compounds and compositions of the present invention arealso useful to treat acute or transient disorders in insulinsensitivity, such as sometimes occur following surgery, trauma,myocardial infarction, and the like. The compounds and compositions ofthe present invention are also useful for lowering serum triglyceridelevels. Elevated triglyceride level, whether caused by geneticpredisposition or by a high fat diet, is a risk factor for thedevelopment of heart disease, stroke, and circulatory system disordersand diseases. The physician of ordinary skill will know how to identifyhumans who will benefit from administration of the compounds andcompositions of the present invention.

The present invention further provides a method for the treatment and/orprophylaxis of hyperglycemia in a human or non-human mammal whichcomprises administering an effective, non-toxic amount of a compound ofthe general formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof to a hyperglycemic human or non-human mammalin need thereof.

They are useful as therapeutic substances in preventing or treatingSyndrome X, diabetes mellitus and related endocrine and cardiovasculardisorders and diseases in human or non-human animals.

The invention also relates to the use of a compound of Formula I asdescribed above, for the manufacture of a medicament for treating aPPARα or PPARγ mediated condition, separately or in combination.

A therapeutically effective amount of a compound of Structural Formula Ican be used for the preparation of a medicament useful for treatingSyndrome X, diabetes, treating obesity, lowering tryglyceride levels,raising the plasma level of high density lipoprotein, and for treating,preventing or reducing the risk of developing atherosclerosis, and forpreventing or reducing the risk of having a first or subsequentatherosclerotic disease event in mammals, particularly in humans. Ingeneral, a therapeutically effective amount of a compound of the presentinvention (1) typically reduces serum glucose levels, or morespecifically HbAlc, of a patient by about 0.7% or more; (2) typicallyreduces serum triglyceride levels of a patient by about 20% or more, and(3) increases serum HDL levels in a patient. Preferably, HDL levels willbe increased by about 30% or more.

Additionally, an effective amount of a compound of Structural Formula Iand a therapeutically effective amount of one or more active agentsselected from a group consisting of: antihyperlipidemic agent, plasmaHDL-raising agents, antihypercholesterolemic agents, fibrates, vitamins,aspirin, insulin secretogogues, insulin and the like can be usedtogether for the preparation of a medicament useful for theabove-described treatments.

Advantageously, compositions containing the compound of StructuralFormula I or the salts thereof may be provided in dosage unit form,preferably each dosage unit containing from about 1 to about 500 mg beadministered although it will, of course, readily be understood that theamount of the compound or compounds of Structural Formula I actually tobe administered will be determined by a physician, in the light of allthe relevant circumstances.

When used herein Syndrome X includes pre-diabetic insulin resistancesyndrome and the resulting complications thereof, insulin resistance,non-insulin dependent diabetes, dyslipidemia, hyperglycemia obesity,coagulopathy, hypertension and other complications associated withdiabetes. The methods and treatments mentioned herein include the aboveand encompass the treatment and/or prophylaxis of any one of or anycombination of the following: pre-diabetic insulin resistance syndrome,the resulting complications thereof, insulin resistance, Type II ornon-insulin dependent diabetes, dyslipidemia, hyperglycemia, obesity andthe complications associated with diabetes including cardiovasculardisease, especially atherosclerosis.

The compositions are formulated and administered in the same generalmanner as detailed herein. The compounds of the instant invention may beused effectively alone or in combination with one or more additionalactive agents depending on the desired target therapy. Combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains a compound of Structural Formula I and one ormore additional active agents, as well as administration of a compoundof Structural Formula I and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of StructuralFormula I or thereof and an insulin secretogogue such as biguanides,thiazolidinediones, sulfonylureas, insulin, or α-glucosidose inhibitorscan be administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent administered inseparate oral dosage formulations. Where separate dosage formulationsare used, a compound of Structural Formula I and one or more additionalactive agents can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e., sequentially;combination therapy is understood to include all these regimens.

An example of combination treatment or prevention of atherosclerosis maybe wherein a compound of Structural Formula I or salts thereof isadministered in combination with one or more of the following activeagents: antihyperlipidemic agents; plasma HDL-raising agents;antihypercholesterolemic agents, fibrates, vitamins, aspirin, and thelike. As noted above, the compounds of Structural Formula I can beadministered in combination with more than one additional active agent.

Another example of combination therapy can be seen in treating diabetesand related disorders wherein the compounds of Structural Formula I,salts thereof can be effectively used in combination with, for example,sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors,other insulin secretogogues, insulin as well as the active agentsdiscussed above for treating atherosclerosis.

The compounds of the present invention, and the pharmaceuticallyacceptable salts, solvates and hydrates thereof, have valuablepharmacological properties and can be used in pharmaceuticalcompositions containing a therapeutically effective amount of a compoundof the present invention, or pharmaceutically acceptable salts, estersor prodrugs thereof, in combination with one or more pharmaceuticallyacceptable excipients. Excipients are inert substances such as, withoutlimitation carriers, diluents, fillers, flavoring agents, sweeteners,lubricants, solubilizers, suspending agents, wetting agents, binders,disintegrating agents, encapsulating material and other conventionaladjuvants. Proper formulation is dependent upon the route ofadministration chosen. Pharmaceutical compositions typically containfrom about 1 to about 99 weight percent of the active ingredient whichis a compound of the present invention.

Preferably, the pharmaceutical composition is in unit dosage form. A“unit dosage form” is a physically discrete unit containing a unit dose,suitable for administration in human subjects or other mammals. Forexample, a unit dosage form can be a capsule or tablet, or a number ofcapsules or tablets. A “unit dose” is a predetermined quantity of theactive compound of the present invention, calculated to produce thedesired therapeutic effect, in association with one or morepharmaceutically-acceptable excipients. The quantity of activeingredient in a unit dose may be varied or adjusted from about 0.1 toabout 1000 milligrams or more according to the particular treatmentinvolved.

The dosage regimen utilizing the compounds of the present invention isselected by one of ordinary skill in the medical or veterinary arts, inview of a variety of factors, including, without limitation, thespecies, age, weight, sex, and medical condition of the recipient, theseverity of the condition to be treated, the route of administration,the level of metabolic and excretory function of the recipient, thedosage form employed, the particular compound and salt thereof employed,and the like.

Preferably, the compounds of the present invention are administered in asingle daily dose, or the total daily dose may be administered individed doses, two, three, or more times per day. Where delivery is viatransdermal forms, of course, administration is continuous.

Suitable routes of administration of pharmaceutical compositions of thepresent invention include, for example, oral, eyedrop, rectal,transmucosal, topical, or intestinal administration; parenteral delivery(bolus or infusion), including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections. The compounds of the invention can also beadministered in a targeted drug delivery system, such as, for example,in a liposome coated with endothelial cell-specific antibody.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, powders, sachets,granules, dragees, capsules, liquids, elixers, tinctures, gels,emulsions, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compound with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores.

For oral administration in the form of a tablet or capsule, the activeingredient may be combined with an oral, non-toxic,pharmaceutically-acceptable carrier, such as, without limitation,lactose, starch, sucrose, glucose, methyl cellulose, calcium carbonate,calcium phosphate, calcium sulfate, sodium carbonate, mannitol,sorbitol, and the like; together with, optionally, disintegratingagents, such as, without limitation, cross-linked polyvinyl pyrrolidone,maize, starch, methyl cellulose, agar, bentonite, xanthan gum, alginicacid, or a salt thereof such as sodium alginate, and the like; and,optionally, binding agents, for example, without limitation, gelatin,acacia, natural sugars, beta-lactose, corn sweeteners, natural andsynthetic gums, acacia, tragacanth, sodium alginate,carboxymethyl-cellulose, polyethylene glycol, waxes, and the like; and,optionally, lubricating agents, for example, without limitation,magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodiumbenzoate, sodium acetate, sodium chloride, talc, and the like. When adosage unit form is a capsule, it may contain, in addition to materialsof the above type, a liquid carrier such as a fatty oil.

Solid form formulations include powders, tablets and capsules. A solidcarrier can be one or more substance which may also act as flavoringagents, lubricants, solubilisers, suspending agents, binders, tabletdisintegrating agents and encapsulating material.

In powders, the carrier is a finely divided solid which is in admixturewith the finely divided active ingredient. In tablets, the activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Sterile liquid formulations include suspensions, emulsions, syrups, andelixirs. The active ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent, or a mixture of both sterile water and sterile organicsolvent.

The active ingredient can also be dissolved in a suitable organicsolvent, for example, aqueous propylene glycol. Other compositions canbe made by dispersing the finely divided active ingredient in aqueousstarch or sodium carboxymethyl cellulose solution or in a suitable oil.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

All formulations for oral administration should be in dosages suitablefor such administration. Particularly suitable compositions for oraladministration are unit dosage forms such as tablets and capsules.

For parental administration the compounds of the present invention, orsalts thereof, can be combined with sterile aqueous or organic media toform injectable solutions or suspensions. Formulations for injection maybe presented in unit dosage form, such as in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The pharmaceutical forms suitablefor injectable use include sterile aqueous solutions or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersions. In all cases, the form must be sterile andmust be fluid to the extent that each syringability exists. It must bestable under the conditions of manufacture and storage and must bepreserved against any contamination. The carrier can be solvent ordispersion medium containing, for example, water, preferably inphysiologically compatible buffers such as Hanks's solution, Ringer'ssolution, or physiological saline buffer, ethanol, polyol (e.g.glycerol, propylene glycol and liquid polyethylene glycol), propyleneglycol and liquid polyethylene glycol), suitable mixtures thereof, andvegetable oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The injectable solutions prepared in this manner can then beadministered intravenously, intraperitoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in a conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of a dry powderinhaler, or an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Pharmaceutical compositions of the present invention can be manufacturedin a manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes.

In making the compositions of the present invention, the activeingredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, lyophilized solid or paste, semi-solid, orliquid material which acts as a vehicle, or can be in the form oftablets, pills, powders, lozenges, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium), orointment, containing, for example, up to 10% by weight of the activecompound. The compounds of the present invention are preferablyformulated prior to administration.

The following pharmaceutical formulations 1 through 8 are illustrativeonly and are not intended to limit the scope of the invention in anyway. “Active Ingredient”, refers to a compound according to StructuralFormula I or salts thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/tablet) Active Ingredient 250 Cellulose, microcrystalline400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mgThe components are blended and compressed to form tablets each weighing665 mg

Formulation 3

An aerosol solution is prepared containing the following components:

Weight Active Ingredient 0.25 Ethanol 25.75 Propellant 22(Chlorodifluoromethane) 74.00 Total 100.00The Active Ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

Tablets, each containing 60 mg of Active ingredient, are made asfollows:

Active Ingredient 60 mg Starch 45 mg Macrocrystalline cellulose 35 mgPolyvinylpyrrolidone (as 10% solution in water) 4 mg Sodiumcarboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total150 mgThe Active Ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

Formulation 5

Capsules, each containing 80 mg of Active Ingredient, are made asfollows:

Active Ingredient 80 mg Starch 59 mg Macrocrystalline cellulose 59 mgMagnesium stearate 2 mg Total 200 mgThe Active Ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation 6

Suppositories, each containing 225 mg of Active Ingredient, are made asfollows:

Active Ingredient 225 mg Saturated fatty acid glycerides 2,000 mg Total2,225 mgThe Active Ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

Suspensions, each containing 50 mg of Active Ingredient per 5 ml dose,are made as follows:

Active Ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified waterto total 5 mlThe Active Ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 8

An intravenous formulation may be prepared as follows:

Active Ingredient 100 mg Isotonic saline 1,000 mlThe solution of the above materials generally is administeredintravenously to a subject at a rate of 1 ml per minute.In yet another embodiment of the compounds of the present invention, thecompound is radiolabelled, such as with carbon-14, or tritiated. Saidradiolabelled or tritiated compounds are useful as reference standardsfor in vitro assays to identify new PPARα and PPARγ agonists.

Synthesis

Compounds of the present invention have been formed by reacting a2-(R1-substituted)-5-R2-substituted-oxazol-4-yl ethyl sulfonyl esterwith a 2-R4-substituted-(4-phenoxy)-alkanoic acid ester. Generally, thesulfonyl ester chemical intermediates have been synthesized through twodifferent routes, shown in Schemes IA and IB, while Scheme II is typicalof the synthetic method used to make the propionic acid chemicalintermediate. The formation of the compounds of the present inventionfrom these chemical intermediates is shown in Scheme III.

In Scheme IA, the first step is a condensation of a dionemonooximerepresented by Structural Formula IA-1 with a R1-substituted aldehyderepresented by Structural Formula IA-2 in the presence of an acid suchas aqueous concentrated hydrochloric acid or, preferably, acetic acidwhich is saturated with hydrogen chloride gas. Typically, hydrogenchloride is bubbled through a solution of the dionemonooxime and theR1-substituted aldehyde in acetic acid, which is held at a constanttemperature of about 0° C. to about 20° C. for about 15 minutes to about1 hour. The product of the condensation is an oxazole n-oxiderepresented by Structural Formula IA-3.

The oxazole n-oxide is then treated with phosphorous oxyhalide, such asphosphorous oxychloride or phosphorous oxybromide in an inert solventsuch as dichloromethane or chloroform to form a2-(R1-substituted)-4-halomethyl-oxazole represented by StructuralFormula IA-4. The reaction typically is carried out at the refluxtemperature of the solvent used and is complete in about 15 minutes toabout 1 hour.

The 2-(R1-substituted)-4-chloromethyl-oxazole is then treated with acyanide and an iodide salt to form a2-(R1-substituted)-4-cyanomethyl-oxazole represented by StructuralFormula IA-5. The reaction is typically carried out in a polar, aproticsolvent such as dimethylformamide at a temperature of about 80° C. toabout 120° C. for about 1 hour to about 6 hours. Preferably, the cyanideand iodide salts are potassium cyanide and potassium iodide.

The cyano group of the a 2-(R1-substituted)-4-cyanomethyl-oxazole isconverted to a carboxylic acid group by treatment with a alkali metalhydroxide to form a 2-(R1-substituted)-4-carboxymethyl-oxazolerepresented by Structural Formula IA-6. The reaction is generallycarried out in an aqueous solution at about 80° C. to about 100° C. Theconcentration of the alkali metal hydroxide in the aqueous solution istypically about 25% to about 85% (weight/volume). Preferably, the alkalimetal hydroxide is potassium hydroxide.

The 2-(R1-substituted)-4-carboxymethyl-oxazole is then treated with acarboxylic acid reducing agent, such as borane or lithium aluminumhydride, to form the 2-(R1-substituted)-4-(2-hydroxyethyl)-oxazoleintermediate represented by Structural Formula IA-7. The reaction istypically carried out under anhydrous conditions in an ether solventsuch as tetrahydrofuran (THF), dioxane, or ethyl ether. When borane isthe reducing agent used, it typically forms a complex with the ethersolvent such as a BH₃-THF complex. A solution having a concentration ofabout 0.5 M to about 1.5 M borane complex in the ether solvent is addeddropwise to a solution of 0.1 M to 1.3 M of the2-(R1-substituted)-4-carboxymethyl-oxazole in the ether solvent. Thereaction temperature is about 20° C. to about 40° C. Typically, thereaction is complete in about 1 hour to about 5 hours.

The chemical intermediate, represented by Structural Formula IA-7, isthen converted into a 2-(R1-substituted-oxazol-4-yl)ethyl sulfonyl esterrepresented by Structural Formula IA-8 by treatment with a sulfonylanhydride, such as tosyl anhydride or mesyl anhydride, or a sulfonylhalide, such as tosyl chloride or mesyl chloride, in the presence of abase. The reaction is typically carried out in an aprotic solvent suchas methylene chloride in the presence of aprotic bases such as pyridineand N,N-dimethylaminopyridine (DXAP). The reaction is complete in about0.5 hours to about 5 hours.

In Scheme IB, the first step is a condensation of β-methyl L-aspartaterepresented by Structural Formula IB-1 with a R1-substituted acidchloride in the presence of mild base to form the amide represented byStructural Formula IB-3. Typically, the reaction is carried out in anacetone/water media in the presence of a carbonate base, such aspotassium or sodium carbonate. The R1-substituted acid chloride is addedto a solution of β-methyl L-aspartate in acetone/water at about 0° C. toabout 10° C. and the reaction warms to ambient temperature for about 60minutes to 2 hours.

The acid is then treated with a base such as pyridine and an anhydridesuch as acetic, n-propyl or trifluoro-acetic anhydride to form theR2-substituted ketone represented by Structural Formula IB-4. Thereaction is typically carried out at 90° C. and is complete in about 90minutes to about 2 hours.

Cyclo-dehydration of the R2-substituted ketone is completed with aprotic acid such as sulfuric acid in the presence of acetic anhydride toform the 2-(R1-substituted)-5-(R2-substituted)-oxazole represented byStructural Formula IB-5. Alternatively, the ketone can be treated with aphosphorus oxyhalide, such as phosphorous oxychloride or phosphorousoxybromide in a polar, aprotic solvent such as dimethylformamide. Inboth methods, the reaction is heated to about 90° C. and is complete inabout 15 minutes to 30 minutes.

The 2-(R1-substituted)-5-(R2-substituted)-oxazole is treated withaqueous base, such as aqueous sodium hydroxide in an alcohol solvent atabout 25° C. to about 45° C. for about 30 minutes to form thecorresponding acid. The acid is treated with a carboxylic acid reducingagent, such as borane or lithium aluminum hydride, to form the2-(R1-substituted)-4-(2-hydroxyethyl)-oxazole intermediate representedby Structural Formula IA-7. The reaction is typically carried out asdescribed for the formation of the intermediate represented byStructural Formula IA-7 in Scheme IA.

In one method, shown in Scheme IIA, a2-(bromophenyl-5-R2-substituted-oxazol-4-yl)ethyl sulfonyl ester(Structural Formula IIA-1) is reacted with a phenol (Structural FormulaIIA-2) in the presence of cesium carbonate to form a2-(3-{2-[2-(bromophenyl)-5-substituted-oxazol-4-yl]ethoxy}-2-phenoxy)-alkanoicacid ester (Structural Formula IIA-3).

In Structural Formula IIA-3, R₂, R₃ and R₄ are terms are as previouslydefined for Structural Formulas I-III. The reaction is typically carriedout in a polar, aprotic solvent such as dimethylformamide at about 40°C. to about 70° C. and is allowed to proceed for about 10 hours to about24 hours. The reactants IIA-1 and IIA-2 are present in about equal molaramounts or with about 0.1 M to about 0.5 M excess of the sulfonyl estercompound. The cesium carbonate is present in about one molar equivalentto about 1.5 molar equivalents with respect to the sulfonyl ester.

The2-(3-{2-[2-(bromophenyl)-5-substituted-oxazol-4-yl]ethoxy}-2-phenoxy)-alkanoicacid ester can be treated with a substituted or unsubstituted alkenyl oralkynyl tributyl tin in the presence of Pd(PPh₃)₄ to form2-(3-(2-[2-(alkenylphenyl)-5-substituted-oxazol-4-yl]ethoxy)-2-phenoxy)-alkanoicacid ester or2-(3-{2-[2-(alkynylphenyl)-5-substituted-oxazol-4-yl]ethoxy}-2-phenoxy)-alkanoicacid ester. The reaction is typically carried out at reflux temperaturein a polar, aprotic solvent such as THF, and is complete in about 10hours to about 20 hours. Optionally, the saturated functionality of theR11 substitution can be reduced by hydrogen in the presence of apalladium on carbon catalyst to form the intermediate represented byStructural Formula IIA-5, where R13 is C1-C4 alkyl, substituted orunsubstituted aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl.

In a second method, shown in Scheme IIB, the2-(3-{2-[2-(bromophenyl)-5-substituted-oxazol-4-yl]ethoxy}-2-phenoxy)-alkanoicacid ester can be treated with an arylalcohol in the presence ofpalladium acetate, 2-(di-tert-butylphosphino)biphenyl and potassiumphosphonate to form a2-(3-{2-[2-(aryloxyphenyl)-5-substituted-oxazol-4-yl]ethoxy}-2-phenoxy)-alkanoicacid ester. The reaction is typically carried out in a nonpolar solventsuch as toluene at reflux temperature for about 2 hours to about sixhours.

In a third method, shown in Scheme IIC, a2-(3-{2-[2-(benzyloxyphenyl)-5-substituted-oxazol-4-yl]ethoxy}-2-phenoxy)-alkanoicacid ester, formed as described in Scheme IA and Scheme IIA, is treatedto form the phenol represented by Structural Formula IIC-2. The phenolis then treated with an alkyliodide in the presence of a base, such asaqueous sodium hydroxide, and a phase transfer catalyst, such astetrabutylammonium bromide, to form an alkoxyphenol represented byStructural Formula IIC-3 where R14 is C1-C6 alkyl, cycloalkyl,aryl-C1-C4 alkyl or 1,2,3,4-tetrahydronaphthyl. An alternative methoduses an alcohol in the presence of triphenylphosphine anddiisopropylazodicarboxylate.

The compound represented by Structural Formula IIA-2 can be prepared bythe method depicted in Scheme III. In this method, the benzyloxyphenolrepresented by Structural Formula III-1 is reacted with a α-haloesterrepresented by Structural Formula III-2 in the presence of cesiumcarbonate to form a compound represented by Structural Formula III-3.The reaction is carried out under anhydrous conditions in a polar,aprotic solvent such as dimethylformamide at about 40° C. to about 80°C. The α-haloester and the cesium carbonate are present in about 1-5 toabout 2.5 molar equivalents with respect to the benzyloxyphenol.Typically, the reaction is complete in about 10 hours to about 24 hours.The R4 substitution is introduced by formation of the enolate with alithium alkylamide base, such as LDA, at −78° C. followed by addition ofan unsubstituted or substituted alkyl or benzyl halide and TBAI to formthe intermediate represented by Structural Formula III-4.

The compound represented by Structural Formula III-4 is then treated toremove the benzyl protecting group to form the phenol represented byStructural Formula IIA-2. Methods of removing a benzyl protecting groupfrom a phenol can be found in Green, et al., Protective Groups inOrganic Synthesis, 2^(nd) edition, (1991), John Wiley & Sons, Inc., NewYork, pages 156-158, the entire teachings of which are incorporatedherein by reference. A preferred method of removing a benzyl protectinggroup is by treating the compound represented by Structural FormulaIII-4 with hydrogen in the presence of palladium on carbon (Pd—C)catalyst.

When it is desired to prepare a compound represented by StructuralFormula IIA-2 in which at least one R6 or R7 group is other thanhydrogen, the compound can be prepared by the method depicted in SchemeIV. A benzyloxy-hydroxybenzaldehyde is treated with a Wittig reagent toform an alkenyl-benzyloxyphenol represented by Structural FormulaXXVIII. R16 of the Wittig reagent is a C1-C5 alkyl, an aryl-C1-C5-alkyl,a cycloalkyl-C1-C3-alkyl, or a cycloalkyl. Conditions for carrying out aWittig reaction are known to those skilled in the art. Thealkenyl-benzyloxyphenol is then reacted as described in Scheme III toform the compound represented by Structural Formula IV-4.

Hydrolysis of alkanoic acid esters are typically carried out in analcohol solvent in the presence of an excess of aqueous alkali metalhydroxide. The reaction is heated at about 50° C. to about 60° C. and isallowed to proceed for about 10 hours to about 24 hours to form thealkanoic acids of the present invention.

EXEMPLIFICATION Instrumental Analysis

Infrared spectra were recorded on a Perkin Elmer 781 spectrometer. ¹HNMR spectra were recorded on a Varian 400 MHz spectrometer at ambienttemperature. Data are reported as follows: chemical shift in ppm frominternal standard tetramethylsilane on the δ scale, multiplicity(b=broad, s singlet, d doublet, t=triplet, q=quartet, qn=quintet andm=multiplet), integration, coupling constant (Hz) and assignment. ¹³CNMR were recorded on a Varian 400 MHz spectrometer at ambienttemperature. Chemical shifts are reported in ppm from tetramethylsilaneon the 5 scale, with the solvent resonance employed as the internalstandard (CDCl₃ at 77.0 ppm and DMSO-d₆ at 39.5 ppm). Combustionanalyses were performed by Eli Lilly & Company MicroanalyticalLaboratory. High resolution mass spectra were obtained on VG ZAB 3F orVG 70 SE spectrometers. Analytical thin layer chromatography wasperformed on EM Reagent 0.25 mm silica gel 60-F plates. Visualizationwas accomplished with UV light.

Example 12-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid

Step A2-Methyl-2-(4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)propionicacid ethyl ester

A mixture of the toluene-4-sulfonic acid2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (See Japan Tobacco IncInternational Application WO 9518125) (24 g, 66.9 mmol),2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (See AmericanHome Products U.S. Pat. No. 3,795,691) (12.5 g, 55.71 mmol) and Cs₂CO₃(22.7 g, 69.6 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. Thereaction was partitioned between EtOAc (160 mL) and H₂O (180 mL), andthe aqueous phase extracted with EtOAc (150 mL). The combined organicphases were dried (MgSO₄) and concentrated under reduced pressure to anoil which was purified by column chromatography (1500 mL SiO₂, 10%EtOAc/hexanes to 20% EtOAc/hexanes) to provide2-methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-phenoxy}propionicacid ethyl ester (17.8 g, 78%) as a colorless, viscous oil: Rf=0.48 in35% EtOAc/hexanes; ¹H NMR (400 MHz, CDCl₃) δ 7.99-7.96 (m, 2H),7.43-7.40 (m, 3H), 6.83-6.75 (m, 4H), 4.22 (q, J=9.2 Hz, 2H), 4.18 (t,J=8.8 Hz, 2H), 2.95 (t, J=8.8 Hz, 2H), 2.36 (s, 3H), 1.52 (s, 6H), 1.27(t, J=9.2 Hz, 3H).

Step B2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid

2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid ethyl ester (6.4 g, 15.6 mmol) was dissolved in MeOH (200 mL) and2N NaOH (150 mL) was added. The resulting cloudy solution became clearafter 30 min and the reaction was stirred vigorously overnight. Thesolution was concentrated under reduced pressure, diluted with H₂O (100mL) and acidified to pH=1 with 5N HCl. The mixture was extracted withEtOAc (2×200 mL), dried (MgSO₄), and concentrated under reduced pressureto provide a white solid. The compound was recrystallized from CH₃CN (85mL) to afford the product (4.50 g, 75%) as colorless needles afterdrying at 50° C. under vacuum for 6 h: Rf=0.14 in 35% EtOAc/hexanes; mp129-130° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.98-7.96 (m, 2H), 7.44-7.41 (m,3H), 6.91-6.79 (m, 4H), 4.16 (t, J=8.8 Hz, 2H), 2.99 (t, J=8.8 Hz, 2H),2.38 (s, 3H), 1.53 (s, 6H); ¹³C (100 MHz, CDCl₃) δ 177.2, 159.7, 154.7,148.3, 145.3, 132.4, 130.1, 128.7, 127.2, 126.1, 122.1, 114.9, 79.9,67.0, 26.1, 25.1, 10.2; IR (CHCl₃) 2991, 1775, 1718, 1554, 1506, 1469,1237, 1145, 1023 cm⁻¹; HRMS (TOF) m/e calcd. for C₂₂H₂₄NO₅ (M⁺+1)382.1654, found 382.1628.

Example 2 2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}butyricacid

Step A 4-[2-(4-Benzyloxyphenoxy)ethyl]-5-methyl-2-phenyloxazole

2-(5-Methyl-2-phenyloxazol-4-yl)ethanol [Hulin, et al., J. Med. Chem.(1992) 35(10), 1853-64] (7.42 g, 36.0 mmol), 4-benzyloxyphenol (7.3 g,36.0 mmol) and triphenylphosphine (9.57 g, 36.0 mmol) were dissolved inanhydrous THF (500 mL) and treated with dropwise addition of diisopropylazodicarboxylate (7.18 mL, 36.0 mmol). The reaction mixture was stirredat 20° C. for 18 h under a positive-pressure atmosphere of N₂. Thereaction was partitioned between EtOAc (100 mL) and 0.1 N NaOH (100 mL),and the organic phase washed with water (100 mL) and brine (100 mL). Theorganic layer was dried with Na₂SO₄ and concentrated to a residue whichwas purified by gradient column chromatography (silica column, 100%hexanes to 20% EtOAc/hexanes) to provide a white solid (10.5 g, 76%).R_(f)=0.3 (10% EtOAc/hexanes) ¹H NMR (250 MHz, DMSO-d₆) δ 7.86 (d, 2H),7.41-7.48 (m, 3H), 7.22-7.38 (m, 5H), 6.86 (d, 2H), 6.80 (d, 2H), 4.97(s, 2H), 4.07 (t, 2H), 2.84 (t, 2H), 2.30 (s, 3H).

Step B 4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenol

4-[2-(4-Benzyloxyphenoxy)ethyl]-2-phenyloxazole (7.0 g, 18.8 mmol) wasdissolved in methanol (150 mL) and treated with palladium on carbon (1.0g, 10 mol %) and ammonium formate (20.0 g, 0.32 mol). The suspension washeated at reflux for 8 h and then cooled to ambient temperature. Theresultant suspension was filtered through Celite with a methanol wash,and the filtrate was concentrated to provide a colorless oil (3.72 g,70%). ¹H NMR (250 MHz, CDCl₃) δ 8.84 (s, 1H), 7.81-7.87 (m, 21H),7.41-7.49 (m, 3H), 6.72 (d, 2H), 6.59 (d, 2H), 4.04 (t, 2H), 2.81 (t,2H), 2.30 (s, 3H); MS (EI): 282 (M+H), 280 (M−H).

Step C 2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}butyric acidethyl ester

A solution of 4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenol in dryDMF (3.0 mL) under argon was treated with Cs₂CO₃ (483 mg, 1.5 mmol) then2-bromobutyric acid ethyl ester (350 μL, 2.4 mmol). The reaction mixturewas stirred at 55° C. for 18 h, was allowed to cool to room temperature,diluted with H₂O, saturated with NaCl, and partitioned with ethylacetate. The organic layer was washed with NaHCO₃ then brine, dried(Na₂SO₄), and concentrated in vacuo to give a yellow oil (394 mg). Theproduct was purified by radial chromatography using a 1 mm plate and0-2% ethyl acetate in CH₂Cl₂ to give a yellow oil (216 mg, 88%). ¹H NMR(400 MHz, CDCl₃) δ 1.07 (t, 3H, J=7.33 Hz), 1.22-1.26 (m, 3H), 1.91-1.99(m, 2H), 2.37 (s, 3H), 2.96 (t, 2H, J=6.60 Hz), 4.18-4.25 (m, 5H), 4.44(t, 1H, J=6.35 Hz), 6.81 (s, 4H), 7.42-7.48 (m, 3H), 7.98-8.00 (m, 2H);MS (ES) m/e 410.2 (M+1).

The following compounds were prepared by the same procedure using theappropriate bromoester:

2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acidmethyl ester:

colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 1.60 (d, 3H, J=6.8 Hz), 2.43(s, 3H), 3.10 (brt, 2H, J=5.9 Hz), 4.19 (brt, 2H, J=5.6 Hz), 4.66 (q,1H, J=6.8 Hz), 6.75 (d, 2H, J=9.3 Hz), 6.81 (d, 2H, J=9.3 Hz), 7.42-7.53(m, 3H), 8.18 (d, 2H, J=6.4 Hz).

2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-3-phenyl-propionicacid ethyl ester:

¹H NMR (400 MHz, CDCl₃) 1.13 (t, 3H, J=6.8 Hz), 2.31 (s, 3H), 2.89 (t,2H, J=6.8 Hz), 3.14-3.20 (m, 2H), 4.61-4.64 (m, 4H), 4.63 (dd, 1H,J=5.6, 7.6 Hz), 6.70 (d, 2H, J=8.8 Hz), 6.71 (d, 2H, J=9.8 Hz),7.17-7.25 (m, 5H), 7.35-7.40 (m, 3H), 7.92-7.94 (m, 2H).

Step D 2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}butyric acid

Under N², a solution of2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}butyric acid ethylester (216 mg, 0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) wastreated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at55° C. for 1 h and concentrated in vacuo. The resulting slurry wassuspended in ethyl acetate, acidified to pH 1 with 1N HCl, andpartitioned. The organic layer was washed with brine, dried (Na₂SO₄),and concentrated in vacuo to give a white solid (155 mg, 77%): ¹H NMR(400 MHz, CDCl₃) δ 1.05 (t, 3H, J=7.57 Hz), 1.92-1.96 (m, 2H), 2.35 (s,3H), 2.94 (t, 2H, J=6.35 Hz), 4.16 (t, 2H, J=6.60 Hz), 4.41 (t, 1H,J=6.11 Hz), 6.76-6.83 (m, 4H), 7.39-7.41 (m, 3H), 7.97-7.99 (m, 2H); MS(ES) m/e 382.0 (M+1).

The following compounds were prepared by the same procedure:

Example 2A2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid

mp 135° C.; ¹H NMR (400 MHz, CDCl₃) δ 1.57 (d, 3H, J=6.8 Hz), 2.37 (s,3H), 2.98 (t, 2H, J=6.4 Hz), 3.73 (s, 3H), 4.20 (t, 2H, J=6.4 Hz), 4.63(q, 1H, J=6.8 Hz), 6.80 (s, 4H), 7.42-7.45 (m, 3H), 8.00-8.03 (m, 2H);MS (FIA) m/e 368.1 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 2.28 (s, 3H), 2.87(t, 2H, J=6.3 Hz), 3.18 (d, 2H, J=6.8 Hz), 3.88-3.97 (m, 2H), 4.63 (t,1H, J=6.4 Hz), 6.59 (d, 2H, J=9.3 Hz), 6.68 (d, 2H, J=8.8 Hz), 7.13-7.26(m, 5H), 7.34-7.35 (m, 3H), 7.85-7.87 (m, 2H); MS (FIA) m/e 444.2 (M+1);Anal. Calcd. for C₂₇H₂₅NO₅: C, 73.12; H, 5.68; N, 3.16. Found C, 73.06;H, 5.99; N, 3.25.

Example 2B2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-phenoxy}phenylacetic acid

MS (ES+) m/e 430.1 (M+1), (ES−) m/e 428.2 (M−1) Example 2C2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}acetic acid

MS (ES+) m/e 354.1 (M+1), (ES−) m/e 352.1 (M−1) Example 2D2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-3-methylbutyricacid

MS (ES+) m/e 382.1 (M+1), 396.1 (M+NH₄). Example 2E2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}hexanoic acid

MS (ES+) m/e 409.1 (M+1), 424.9 (M+NH₄). Example 2F2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-phenoxy}octanoic acid

MS (ES+) m/e 438.1 (M+1), 452.2 (M+NH₄). Example 2G2-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-phenoxy}dodecanoic acid

MS (ES+) m/e 494.1 (M+1), 508.3 (M+NH₄). Example 3 Sodium2-methyl-2-{4-[2-(2-phenyloxazol-4-yl)ethoxy]phenoxy}propionate

Step A 4-[2-(2-Phenyloxazol-4-yl)ethoxy]phenol

Made from 4-[2-(4-benzyloxyphenoxy)ethyl]-2-phenyloxazole (Eli Lilly &Company, WO9613264) using the procedure described in Example 2, Step A.¹H NMR (250 MHz, CDCl₃) δ 8.92 (s, 1H), 8.03 (s, 1H), 7.90-8.02 (m, 2H),7.48-7.56 (m, 3H), 6.78 (d, 2H), 6.66 (d, 2H), 4.15 (t, 2H), 2.94 (t,2H). MS (EI): 190 (M+H), 188 (M−H).

Step B 2-Methyl-2-{4-[2-(2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid, ethyl ester

4-[2-(2-Phenyloxazol-4-yl)ethoxy]phenol (3.7 g, 13.0 mmol) and cesiumcarbonate (4.71 g, 14.5 mmol) were suspended in anhydrous DMF (100 mL)and treated with dropwise addition of ethyl 2-bromoisobutyrate (2.54 g,13.0 mmol, 1.93 mL). The reaction mixture was stirred at ambienttemperature for 24 h and then partitioned between ether (200 mL) and 1.0N HCl (200 mL). The organic layer was washed with water (100 mL), driedover MgSO₄ and concentrated to a brown oil, which was purified bygradient column chromatography (200 mL SiO₂, 100% hexanes to 20%EtOAc/hexanes) to provide2-methyl-2-{4-[2-(2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid,ethyl ester (2.54 g,

50%) as a colorless, viscous oil: R_(f)=0.5 in 20% EtOAc/hexanes; ¹H NMR(250 MHz, CDCl₃) δ 7.96-8.02 (m, 2H), 7.37-7.46 (m, 3H), 6.81 (s, 4H),4.32 (q, 2H), 4.20 (t, 2H), 3.03 (t, 2H), 1.52 (s, 6H), 1.27 (t, 3H).

Step C Sodium2-methyl-2-{4-[2-(2-phenyloxazol-4-yl)ethoxy]phenoxy}propionate

2-Methyl-2-{4-[2-(2-phenyloxazol-4-yl)ethoxy]phenoxy}-propionic acid,ethyl ester 2.5 g, 63.2 mmol) was dissolved in MeOH (200 mL) and 2N NaOH(100 mL) was added. The resulting cloudy solution became clear after 30min and the reaction was stirred vigorously for 6 h. The solvents wereremoved, and the residual solids were triturated with water. Thesuspended solids were then collected and triturated with pentane toproduce a white solid (2.38 g, 97%). mp 199-200° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.90-7.93 (m, 2H), 7.46-7.49 (m, 3H), 6.73 (d, J=9.0 Hz, 2H),6.69 (d, J=9.0 Hz, 2H), 4.12 (t, J=6.4 Hz, 2H), 2.91 (t, J=6.4 Hz, 2H),1.26 (s, 3H); MS (EI): 390 (M+H), 366 (M−Na).

Example 42-Methyl-2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenoxy]propionicacid

Step A2-Methyl-2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenoxy]propionicacid, ethyl ester

Made from (5-methyl-2-phenyloxazol-4-yl)methanol [Overman, et al., J.Org. Chem. (1979), 44(13), 2323-25] and ethyl2-(4-hydroxyphenoxy)-2-methylpropanoate (American Home Products, U.S.Pat. No. 3,795,691) via an analogous procedure to that reported forExample 2, Step A: ¹H NMR (300 MHz, CDCl₃) δ 8.03-8.09 (m, 2H),7.45-7.52 (m, 3H), 6.94 (d, 2H), 6.88 (d, 2H), 4.99 (s, 2H), 4.37 (q,2H), 2.47 (s, 3H), 1.60 (s, 6H), 1.33 (t, 3H).

Step B2-Methyl-2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenoxy]propionicacid

Hydrolysis of2-methyl-2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)-phenoxy]propionicacid, ethyl ester was carried out in the manner described in Example 2,Step D: mp 136-138° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.88-7.91 (m, 2H),7.46-7.49 (m, 3H), 6.90 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.89(s, 2H), 2-39 (s, 3H), 1.40 (s, 6H); MS (EI): 368 (M+1), 366 (M−1).

Example 52-Methyl-2-{4-[3-(5-methyl-2-phenyloxazol-4-yl)-allyloxy]phenoxy}propionicacid

Step A 3-(5-Methyl-2-phenyloxazol-4-yl)-acrylic acid, ethyl ester

5-Methyl-2-phenyloxazole-4-carbaldehyde [Hulin, et al., J. Med. Chem.(1992) 35(10), 1853-64] (5.62 g, 30 mmol), triethylphosphonoacetate(6.55 mL, 33 mmol), and LiOH (1.38 g, 33 mmol) were dissolved inanhydrous THF (150 mL) and stirred for 18 h at ambient temperature underan atmosphere of nitrogen. The reaction mixture was then diluted withether (100 mL) and washed with saturated NH₄Cl solution (100 mL), thenwater (100 mL). The aqueous layers were back-extracted with ether (100mL) and the combined organic layers were again washed with water (100mL). The ether layer was dried over MgSO₄ and concentrated. Theresultant residual solids were purified by column chromatography (250 mgsilica, 100% hexanes to 10% EtOAc/hexanes) to provide a whitecrystalline solid (3.46 g, 45%): R_(f)=0.55 (50% hexanes/EtOAc); ¹H NMR(400 MHz, CDCl₃) δ 7.97-8.05 (m, 2H), 7.50 (d, 1H), 7.40-7.44 (m, 3H),6.63 (d, 2H) 4.26 (q, 2H), 2.43 (s, 3H), 1.33 (t, 3H); MS (EI): 258(M+1).

Step B 3-(5-Methyl-2-phenyloxazol-4-yl)-prop-2-en-1-ol

Lithium aluminum hydride (480 mg, 12.6 mmol) was slurried in anhydrousTHF (15 mL) and treated with dropwise addition of a solution of3-(5-methyl-2-phenyloxazol-4-yl)-acrylic acid, ethyl ester (2.60 g, 10.1mmol) at 0° C. The reaction mixture was stirred for 1.5 h at thistemperature and then treated with dropwise addition of isopropanol (1.0mL) followed by water (10 mL). The biphasic suspension was acidifiedwith 0.1 N HCl (10 mL), diluted with ether (20 mL) and partitioned. Theaqueous layer was extracted once with ether (15 mL) and the combinedorganic layers dried over MgSO₄ and concentrated to provide a colorlessoil (1.13 g, 52%): R_(f)=0.18 (50% hexanes/EtOAc); ¹H NMR (300 MHz,CDCl₃) δ 7.99-8.03 (m, 2H), 7.42-7.48 (m, 3H), 6.60 (dt, 1H), 6.47 (d,1H), 4.35 (m, 2H), 3.76 (b, 1H), 2.37 (s, 3H); MS (EI): 216 (M+1).

Step C2-Methyl-2-{4-[3-(5-methyl-2-phenyloxazol-4-yl)-allyloxy]phenoxy}propionicacid, ethyl ester

Synthesized from 3-(5-methyl-2-phenyloxazol-4-yl)-prop-2-en-1-ol andethyl 2-(4-hydroxyphenoxy)-2-methylpropanoate (American Home Products,U.S. Pat. No. 3,795,691) via an analogous procedure to that reported forExample 2, Step A: ¹H NMR (300 MHz, CDCl₃) δ 7.95-7.99 (m, 2H),7.36-7.43 (m, 3H), 6.80 (s, 4H), 6.61 (dt, 1H), 6.49 (d, 1H), 4.62 (d,2H), 4.18 (q, 2H), 2.37 (s, 3H), 1.49 (s, 6H), 1.23 (t, 3H); MS (EI):422 (M+1).

Step D2-Methyl-2-{4-[3-(5-methyl-2-phenyloxazol-4-yl)-allyloxy]phenoxy}propionicacid

Hydrolysis of2-methyl-2-{4-[3-(5-methyl-2-phenyloxazol-4-yl)allyloxy]-phenoxy}propionicacid, ethyl ester was carried out in the manner described in Example 2,Step D: ¹H NMR (300 MHz, DMSO-d₆) δ 7.87-7.93 (m, 2H), 7.41-7.48 (m,3H), 6.85 (d, 2H), 6.77 (d, 2H), 6.64 (d, 1H), 6.41 (dt, 1H), 4.62 (d,2H), 2.38 (s, 3H), 1.37 (s, 6H); MS (EI): 394 (M+1), 392 (M−1).

Example 62-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-3-phenylpropionicacid

Step A 2-2-(4-Benzyloxyphenoxy)-2-methyl-3-phenylpropionic acid, ethylester

2-(4-Benzyloxyphenoxy)propionic acid, ethyl ester [American Cyanamid,U.S. Pat. No. 4,209,651] (2.0 g, 6.66 mmol) dissolved in anhydrous THF(16 mL) was cooled to −78° C. under an atmosphere of nitrogen, andtreated with dropwise addition of lithium diisopropylamide (4.16 mL of a2.0M in THF). After 15 min, benzyl bromide (1.03 mL, 8.66 mmol) wasadded dropwise rapidly followed immediately by addition oftetrabutylammonium iodide (246 mg, 0.7 mmol). The cooling bath wasremoved and the reaction mixture allowed to stir for 14 h whilegradually warming to ambient temperature. The crude reaction mixture waspartitioned between EtOAc (15 mL) and saturated aqueous NH₄Cl (15 mL),and the aqueous layer extracted once with ether (20 mL). The combinedorganic layers were washed with brine (25 mL), dried over MgSO₄ andconcentrated to an oily residue. This material was purified by gradientcolumn chromatography (100 g SiO₂, 100% hexanes to 20% EtOAc/hexanes) toprovide a colorless oil (2.22 g, 85%): R_(f)=0.45 (20% EtOAc/hexanes);¹H NMR (300 MHz, CDCl₃) δ 7.10-7.40 (m, 10H), 6.80 (d, 2H), 6.76 (d,2H), 4.97 (s, 2H), 4.18 (q, 2H), 3.26 (d, 1H), 3.13 (d, 1H), 1.28 (s,3H), 1.21 (t, 3H); MS (EI): 391 (M+1).

Step B 2-(4-Hydroxyphenoxy)-2-methyl-3-phenylpropionic acid, ethyl ester

Debenzylation of 2-(4-benzyloxyphenoxy)-2-methyl-3-phenylpropionic acid,ethyl ester was achieved in the manner described in Example 2, Step B.¹H NMR (300 MHz, CDCl₃) δ 7.20-7.28 (m, 5H), 6.73 (d, 2H), 6.66 (d, 2H),4.71 (b, 1H), 4.11 (q, 2H), 3.26 (d, 1H), 3.12 (d, 1H), 1.30 (s, 3H),1.24 (t, 3H); MS (EI): 301 (M+1), 299 (M−1)

Step C2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-3-phenylpropionicacid, ethyl ester

Mitsunobu coupling of 2-(4-hydroxyphenoxy)-2-methyl-3-phenylpropionicacid, ethyl ester and 2-(5-methyl-2-phenyloxazol-4-yl)ethanol [Hulin, etal., J. Med. Chem. (1992) 35(10), 1853-64] in the manner described inExample 2, Step A. ¹H NMR (300 MHz, CDCl₃) δ 7.89-7.93 (m, 2H),7.33-7.41 (m, 3H), 7.19-7.23 (m, 5H), 6.74 (d, 2H), 6.70 (d, 2H), 4.17(q, 2H), 4.13 (t, 2H), 3.24 (d, 1H), 3.09 (d, 1H), 2.91 (t, 2H), 2.32(s, 3H), 1.25 (s, 3H), 1.21 (t, 3H); MS (EI): 486 (M+1).

Step D2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-3-phenylpropionicacid

Hydrolysis of2-methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-3-phenylpropionic acid ethyl ester was carried out in the manner described inExample 2, Step D. ¹H NMR (300 MHz, DMSO-d₆) δ 13.0 (b, 1H), 7.88-7.93(m, 2H), 7.48-7.55 (m, 3H), 7.22-7.32 (m, 5H), 6.83 (d, 2H), 6.74 (d,2H), 4.13 (t, 2H), 3.20 (d, 1H), 3.08 (d, 1H), 2.91 (t, 2H), 2.34 (s,3H), 1.21 (s, 3H); MS (EI): 458 (M+1).

Example 72-Methyl-2-{4-[2-(2-phenyl-5-propyloxazol-4-yl)-ethoxy]phenoxy}propionicacid

Step A 4-(2-Benzyloxyethyl)-2-phenyloxazole

To a solution of 2-(2-phenyloxazol-4-yl)-ethanol (Eli Lilly and Co. WO9613264)(500 mg, 2.64 mmol) in THF (8 mL) was added NaH (215 mg, 5.28mmol), followed by tetrabutyl-ammonium iodide (96 mg, 0.26 mmol). After10 min, benzyl bromide (677 mg, 3.96 mmol, 0.47 mL) was added viasyringe. After 3 h, the reaction was partitioned between H₂O (20 mL) anddiethyl ether (20 mL). The organic phase was washed with brine and thenthe combined aqueous phases were hack extracted with ether (50 mL). Theorganic phases were dried (MgSO₄), filtered and concentrated. Theproduct was purified by flash chromatography (80 mL SiO₂, 25%EtOAc/hexanes) and obtained as a colorless oil (690 mg, 93%): Rf=0.46 in25% EtOAc/hexanes; ¹H NMR (500 MHz, CDCl₃) δ 8.03-8.01 (m, 2H), 7.52 (t,J=1.0 Hz, 1H), 7.45-7.41 (m, 3H), 7.34-7.33 (m, 3H), 7.29-7.26 (m, 1H),4.57 (s, 2H), 3.80 (t, J=7.0 Hz, 2H), 2.93 (t, J=7.0 Hz, 2H); ¹³C (125MHz, CDCl₃) δ 161.3, 139.3, 138.2, 135.0, 130.1, 128.7, 128.4, 127.7,127.6, 126.3, 73.0, 68.5, 27.3.

Step B 4-(2-Benzyloxyethyl)-2-phenyl-5-propyloxazole

4-(2-Benzyloxyethyl)-2-phenyloxazole (670 mg, 239 mmol) was dissolved inTHF (10 mL) and cooled to −78° C. before adding n-butyllithium (1.15 mLof a 2.5 M solution in hexanes). The resulting orange solution waswarmed to −65° C., stirred 45 min, and then propyl iodide (1.22 g, 7.17mmol, 0.70 mL) was added via syringe. The solution was warmed to ambienttemperature and stirred 90 min. The mixture was concentrated and theproduct purified by flash chromatography (100 mL SiO₂, hexanes to 20%EtOAc/hexanes) and obtained as a colorless oil (340 mg, 44%): Rf=0.49 in20% EtOAc/hexanes; ¹H NMR (500 MHz, CDCl₃) δ 8.00-7.96 (m, 2H),7.42-7.26 (m, BH), 4.54 (s, 2H), 3.76 (t, J=7.0 Hz, 2H), 2.83 (t, J=7.0Hz, 2H), 2.64 (t, J=7.0 Hz, 2H) 1.68 (sextet, J=7.0 Hz, 2H), 0.96 (t,J=7.0 Hz, 3H).

Step C 2-(2-Phenyl-5-propyloxazol-4-yl)ethanol

4-(2-Benzyloxyethyl)-2-phenyl-5-propyloxazole (340 mg, 1.05 mmol) wasdissolved in THF (5 mL) and treated with Pearlman's catalyst (170 mg).The solution was stirred vigorously under a hydrogen atmosphere (1 atm)for 90 min, and then the mixture was filtered through celite. The celitewas rinsed with CH₂Cl₂ and the solution dried (MgSO₄), filtered andconcentrated to a clear, colorless oil: Rf=0.25 in 60% EtOAc/hexanes; ¹HNMR (300 MHz, CDCl₃) δ 8.00-7.96 (m, 2H), 7.44-7.22 (m, 2H), 3.92 (br s,2H), 2.73 (t, J=5.5 Hz, 2H), 2.65 (t, J=7.0 Hz, 2H) 1.70 (sextet, J=7.0Hz, 2H), 0.98 (t, J=7.0 Hz, 3H).

Step D2-Methyl-2-{4-[2-(2-phenyl-5-propyloxazol-4-yl)-ethoxy]phenoxy}propionicacid ethyl ester

2-(2-Phenyl-5-propyloxazol-4-yl)ethanol (225 mg, 0.97 mmol) and triethylamine (167 mg, 1.65 mmol, 0.23 mL) were dissolved in CH₂Cl₂ (3.5 mL) at0° C. and treated with methane sulfonyl chloride (167 mg, 1.46 mmol,0.11 mL). After 1 h, NH₄Cl (25 mL of a 10% aqueous solution) was addedand then the organic phase was dried (MgSO₄), filtered and concentratedto an oil. The intermediate mesylate was combined with Cs₂CO₃ (383 mg,1.18 mmol), and 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester(American Home Products U.S. Pat. No 3,795,691) (190 mg, 0.84 mmol) inDMF (4 mL) and heated to 55° C. After 18 h, the reaction mixture waspartitioned between H₂O (25 mL) and EtOAc (25 mL) and then the organicphase washed with H₂O (2×), dried (MgSO₄), filtered and concentrated.The product was purified by flash chromatography (70 mL/SiO₂, hexanes to20% EtOAc/hexanes) and obtained as a colorless oil (170 mg, 46%):Rf=0.49 in 20% EtOAc/hexanes; ¹H NMR (500 MHz, CDCl₃) δ 8.00-7.96 (m,2H), 7.42-7.38 (m, 3H), 6.83-6.76 (m, 4H), 4.22 (q, J=7.0 MHz, 2H), 4.19(t, J=7.0 Hz, 2H), 2.95 (t, J=7.0 Hz, 2H), 2.67 (t, J=7.0 Hz, 2H) 1.71(sextet, J=7.0 Hz, 2H), 1.52 (s, 6H), 1.26 (t, J=7.0 Hz, 3H), 0.96 (t,J=7.0 Hz, 3H).

Step E2-Methyl-2-{4-[2-(2-phenyl-5-propyloxazol-4-yl)-ethoxy]phenoxy}propionicacid

2-Methyl-2-{4-[2-(2-phenyl-5-propyloxazol-4-yl)-ethoxy]phenoxy}propionicacid ethyl ester (170 mg, 0.39 mmol) was hydrolyzed as described inExample 1 to provide the product as a pale yellow oil: ¹H NMR (400 MHz,CDCl₃) δ 10.85 (br s, 1H), 8.04-8.00 (m, 2H), 7.44-7.42 (m, 3H),6.91-6.72 (m, 4H), 4.16 (t, J=6.1 Hz, 2H), 3.04 (t, J=6.1 Hz, 2H), 2.70(t, J=7.0 Hz, 2H) 1.73 (sextet, J=7.0 Hz, 2H), 1.53 (s, 6H), 1.01 (t,J=7.0 Hz, 2H).

Example 82-(4-{2-[2-(3,5-Di-tert-butyl-4-hydroxyphenyl)oxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

Step A2-(4-{2-[2-(3,5-Di-tert-butyl-4-hydroxyphenyl)oxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester

Toluene-4-sulfonic acid2-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)oxazol-4-yl]ethyl ester (EliLilly and Co, Eur. Pat. Appl. 98-308063) (490 mg, 1.04 mmol) was coupledto 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (AmericanHome Products U.S. Pat. No. 3,795,691) (203 mg, 0.90 mmol) following theprocedure described in Example 1 to provide the product (330 mg, 70%) asa clear, colorless oil: Rf=0.55 in 35% EtOAc/hexanes; ¹H NMR (500 MHz,CDCl₃) δ 7.84 (s, 2H), 7.49 (s, 1H), 6.83-6.80 (m, 4H), 5.50 (s, OH),4.23 (q, J=7.0 MHz, 2H), 4.22 (t, J=6.0 Hz, 2H), 3.04 (t, J=6.0 Hz, 2H),1.53 (s, 6H), 1.48 (s, 18H), 1.27 (t, J=7.0 Hz, 3H).

Step B2-(4-{2-[2-(3,5-Di-tert-butyl-4-hydroxyphenyl)oxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

2-(4-{2-[2-(3,5-Di-tert-butyl-4-hydroxyphenyl)oxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester (320 mg, 0.61 mmol) was hydrolyzed following theprocedure described in Example 1 to provide the product (191 mg, 63%) asa white solid: Rf=0.07 in 40% EtOAc/hexanes; ¹H NMR (500 MHz, CDCl₃) δ7.83 (s, 2H), 7.50 (s, 1H), 6.92-6.80 (m, 4H), 5.51 (s, OH), 4.19 (t,J=6.5 Hz, 2H), 3.07 (t, J=6.5 Hz, 2H), 1.53 (s, 6H), 1.48 (s, 18H).

Example 92-(4-{2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

Step A 2-(4-Bromophenyl)-4,5-dimethyloxazole-3-oxide

A solution of 2,3-butanedione monooxime (50 g, 0.49 mol) and4-bromobenzaldehyde (101 g, 0.54 mol) in acetic acid (500 mL) was cooledto 0° C. and then gaseous HCl was bubbled through the solution for 35min while the reaction was stirred in an ice bath. Diethyl ether (500mL) was then added to the reaction to precipitate the product and theresultant slurry stirred 45 min at 0° C. before being filtered. Thesolids were rinsed with Et₂O (50 mL), taken up in water (1 L) and conc.NH₄OH (60 mL) added to the slurry. This mixture was extracted withCHCl₃, the organic layer was dried (MgSO₄), and the solvent removed invacuo to give 97.4 g (74%) of2-(4-bromophenyl)-4,5-dimethyloxazole-3-oxide as a white solid. Thecompound should be used directly with 24-48 h: ¹H NMR (500 MHz, CDCl₃) δ8.34 (d, J=9.0 Hz, 2H), 7.61 (d, J=9.0 Hz, 2H), 2.35 (s, 3H), 2.90 (s,3H); ¹³C (125 MHz, CDCl₃) δ 142.1, 131.9, 129.5, 126.3, 124.1, 122.2,11.1, 6.2; IR (KBr) 1685, 1529, 1418, 1377, 1233, 1165 cm⁻¹; UV (EtOH)λ_(max) 307 nm (ε 24371); HRMS (TOF) m/z calc'd for C₁₁H₁₁ ⁷⁹BrNO₂:267.997, found 267.9951.

Using 3-bromobenzaldehyde, 2-thiophenecarboxaldehyde, and4-benzyloxybenzaldehyde, respectively, the following compounds wereprepared by the same procedure:

-   2-(3-Bromophenyl)-4,5-dimethyloxazole-3-oxide:

¹H NMR (300 MHz, CDCl₃) δ 8.06 (s, 1H), δ 8.40 (d, J=8.0 Hz, 1H), 7.55(d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 2.39 (s, 3H), 2.20 (s, 3H).

-   2-(4-Benzyloxy-phenyl)-4,5-dimethyl-oxazole-N-oxide:

¹H NMR (500 MHz, CDCl₃) δ 8.40-8.38 (m, 2H), 7.40-7.29 (m, 5H),7.05-7.02 (m, 2H), 5.07 (s, 2H), 2.29 (s, 3H), 2.16 (s, 3H).

Step B 2-(4-Bromophenyl)-4-(chloromethyl)-5-methyloxazole

A solution of 2-(4-bromophenyl)-4,5-dimethyl-oxazole-3-oxide

(96.6 g, 0.36 mol) in CHCl₃ (0.90 L) was treated dropwise withphosphorous oxychloride (61.1 g, 0.40 mol) allowing the reaction toexotherm and then stir at reflux for 30 min. The reaction was thencooled to rt and washed with water (2×1 L). The combined aqueous washeswere back extracted with CH₂Cl₂ (2×400 mL). The organic layers weredried (MgSO₄), and the solvent removed in vacuo to give crude productthat was recrystallized from hot hexanes (300 mL), decanting the hotsupernate away from a dark oily material. The remaining dark oil wasagitated in additional hot hexanes (200 mL) and the combined supernateswere cooled to 0° C. to crystallize the product which was isolated byfiltration to give 74.2 g (72%) of2-(4-bromophenyl)-4-(chloromethyl)-5-methyloxazole as a lime-greenpowder: Rf=0.39 in 20% EtOAc/hexanes; ¹H NMR (500 MHz, CDCl₃) δ7.88-7.86 (m, 2H), 7.59-7.56 (m, 2H), 4.54 (s, 2H), 2.42 (s, 3H); ¹³C(125 MHz, CDCl₃) δ 159.2, 146.9, 133.2, 132.0, 127.6, 126.1, 124.7,37.1, 11.5; IR (KBr) 2970, 1633, 1599, 1481, 1401, 1258, 1117, 1008cm⁻¹; UV (EtOH) λ_(max) 281 nm (ε 21349); HRMS (FAB) m/z calc'd forC₁₁H₁₀ ⁷⁹BrClNO: 285.9634, found 285.9641; Anal. Calc'd for C₁₁H₉ClBrNO:C, 46.11; H, 3.17; N, 4.89; Cl, 12.37; Br, 27.88. Found C, 46.28; H,3.07; N, 4.81; Cl, 12.36; Br, 27.88.

The following compounds were also prepared by this procedure:

2-(3-Bromophenyl)-4-(chloromethyl)-5-methyloxazole:

¹H NMR (300 MHz, d₆-DMSO) δ 8.19 (s, 1H), 7.93 (d, J=8.0, 1H), 7.58 (d,J=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 4.45 (s, 2H), 2.41 (s, 3H).

2-(4-Benzyloxy-phenyl)-4-chloromethyl-5-methyl-oxazole

¹H NMR (500 MHz, CDCl₃) δ 7.92-7.90 (m, 2H), 7.42-7.31 (m, 5H),7.00-6.98 (m, 2H), 5.08 (s, 2H), 4.51 (s, 2H), 2.37 (s, 3H); ¹³C (125MHz, CDCl₃) δ 160.6, 145.9, 136.5, 132.5, 128.9, 128.5, 128.1, 127.9,127.5, 120.1, 115.1, 70.1, 37.2, 11.2; IR (CHCl₃) 1637, 1611, 1499,1454, 1246, 1168, 1010, 1004, 836, 750, 696 cm⁻¹; UV (EtOH) λ_(max) 2825nm (ε 32622); HRMS (ES⁺) m/z exact mass calcd for C₁₈H₁₇NO₂Cl 314.0948,found 314.0939; Anal. Calc'd for C₁₆H₁₆NO₂Cl: C, 68.90; H, 5.14; N,4.46; Cl, 11.30. Found C, 68.70; H, 5.00; N, 3.97; Cl, 11.32.

Step C 2-(4-Bromophenyl)-5-methyl-4-oxazoleacetic acid

To a solution of 2-(4-bromophenyl)-4-(chloromethyl)-5-methyloxazole

(64.8 g, 0.23 mol) in DMF (400 mL) was added powdered potassium cyanide(22.1 g, 0.34 mol) and potassium iodide (28.6 g, 0.17 mol) and theresultant mixture heated to 85° C. for 3.5 h. The reaction mixture wasthen cooled to rt. Potassium carbonate (5 g) was dissolved in water (800mL) and added dropwise to the reaction to precipitate the product (stirvigorously 15 min following addition) which was isolated by filtrationand washed with water (2×400 mL). The crude[2-(4-bromophenyl)-5-methyloxazole-4-yl]-acetonitrile was carried on asis in the next step without purification. ¹H NMR (300 MHz, CDCl₃) δ 7.85(m, 2H), 7.58 (m, 2H), 3.64 (s, 2H), 2.43 (s, 3H).

The crude [2-(4-bromophenyl)-5-methyloxazole-4-yl]-acetonitrile

(assume 0.22 mol) was combined with 2-methoxyethanol (630 mL) and 85%solid KOH (74.6 g, 1.33 mol) in water (360 mL) was added to thereaction. The mixture was heated to reflux for 3 h, cooled, quenchedwith 2 M HCl (500 mL), and extracted with CH₂Cl₂. The organic layer wasdried (MgSO₄), and the solvent removed in vacuo, using toluene toazeotropically remove residual 2-methoxyethanol. The crude product (57-3g) was recrystallized from toluene (450 mL) to give 39.8 g (60%) of2-(4-bromophenyl)-5-methyl-4-oxazoleacetic acid as an off-white powder:Rf=0.23 in 10% MeOH/CH₂Cl₂; ¹H NMR (500 MHz, CDCl₃) δ 9.00 (br s, 1H),7.85-7.83 (m, 2H), 7.58-7.56 (m, 2H), 3.62 (s, 2H), 2.36 (s, 3H); ¹³C(125 MHz, CDCl₃) δ 173.8, 159.0, 146.2, 132.0, 129.1, 127.6, 125.9,124.7, 31.5, 10.2; IR (CHCl₃) 2923, 1699, 1641, 1481, 1428, 1306, 1234,1010, 829, 727 cm⁻¹.

The following compounds were prepared by the same procedure.

[2-(3-Bromophenyl)-5-methyloxazole-4-yl]-acetonitrile

¹H NMR (300 MHz, d₆-DMSO) δ 8.00 (t, J=1.83 Hz, 1H), 7.90 (dt, J=8.2,1.2 Hz, 1H), 7.70 (ddd, J=8.0, 1.8, 1.2 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H),4.01 (s, 2H), 2.41 (s, 3H).

2-(3-Bromophenyl)-5-methyl-4-oxazoleacetic acid

¹H NMR (300 MHz, dr-DMSO) δ 7.99 (t, J=1.83 Hz, 1H), 7.88 (dt, J=8.1,1.5 Hz, 1H), 7.65 (ddd, J=8.1, 1.8, 1.5 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H),3.50 (s, 2H), 2.35 (s, 3H).

(5-Methyl-2-thiophen-2-yl-oxazol-4-yl)-acetonitrile. mp 82-84° C.; ¹HNMR (500 MHz, CDCl₃) δ 7.60 (m, 1H), 7.40 (m, 1H), 7.08 (m, 1H), 3.60(s, 2H) 2.40 (s, 3H)

(5-Methyl-2-thiophen-2-yl-4-oxazoleacetic acid. mp 185° C.; ¹H NMR (500MHz, CDCl₃) δ 7.65 (m, 1H), 7.40 (m, 1H), 7.08 (m, 1H), 3.60 (s, 2H),2.31 (s, 3H). [2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-acetic acid

¹H NMR (500 MHz, CDCl₃) 7.91 (d, 2H, J=8.21 Hz), 7.45-7.27 (m, 5H), 7.03(d, 2H, J=8.21 Hz), 5.11 (s, 2H), 3.60 (s, 3H), 2.34 (s, 3H); ¹³C (125MHz, CDCl₃) δ 171.5, 159.8, 158.2, 144.9, 136.6, 129.9, 128.4, 127.9,127.7, 127.1, 119.9, 115.2, 69.4, 31.6, 9.7; IR (CHCl₃) 1711, 1611,1501, 1293, 1257, 1216, 834, 742 cm⁻¹; UV (EtOH) λ_(max) 285 nm (ε25018); HRMS (ES⁺) m/z exact mass calcd for C₁₉H₁₈NO₄ 324.1236, found324.1265; Anal. Calc'd for C₁₉H₁₇NO₄: C, 70.58; H, 5.30; N, 4.33. FoundC, 69.69; H, 5.26; N, 4.34

Step D 2-(4-Bromophenyl)-5-methyl-4-oxazoleethanol

A solution of 2-(4-bromophenyl)-5-methyl-4-oxazoleacetic acid (39.1 g,0.13 mol) in dry THF (175 mL) was treated dropwise with borane-THFcomplex (227 mL of a 1.0 M solution in THF, 1.3 mol) over 2 h (reactiontemperature to 35° C.). After stirring 2 h at rt under N₂, the reactionwas quenched with slow addition of methanol (60 mL) and stirredovernight at rt. The reaction was diluted with 1 N NaOH (50 mL) andextracted with CH₂Cl₂ (2×200 mL). The organic layer was washed with H₂O(3×100 mL), dried (MgSO₄), and the solvent removed in vacuo to give 38.7g of crude product that was recrystallized from toluene (200 mL, washsolid with cold hexanes) to give 26.9 g (72%) of2-(4-bromophenyl)-5-methyl-4-oxazoleethanol as a white powder: Rf=0.37in 10% MeOH/CH₂Cl₂; ¹H NMR (500 MHz, CDCl₃) δ 7.84-7.82 (m, 2H),7.57-7.55 (m, 2H), 3.91 (q, J=5.5 Hz, 2H), 3.14 (t, J=6.0 Hz, OH), 2.72(t, J=5.5 Hz, 2H), 2.33 (s, 3H) ¹³C (125 MHz, CDCl₃) δ 158.7, 144.5,134.2, 131.9, 127.4, 126.4, 124.3, 61.8, 28.1, 10.1; IR (KBr) 3293,2948, 1642, 15985, 1480, 1472, 1401, 1053, 1003, 836, 734 cm⁻¹; Anal.Calc'd for C₁₂H₁₂BrNO₂: C, 51.09; H, 4.29; N, 4.96; Br, 28.32. Found C,51.31; H, 4.06; N, 4.90; Br, 28.19.

The following compounds were prepared by the same procedure.

2-(3-Bromophenyl)-5-methyl-4-oxazoleethanol

mp 92-93° C.; ¹H NMR (300 MHz, d₆-DMSO) δ 7.99 (s, 1H), 7.88 (d, J=7.7Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 4.61 (t, J=5.5Hz, OH), 3.63 (q, J=5.5 Hz, 2H), 2.60 (t, J=6.6 Hz, 2H), 2.32 (s, 3H).

2-(5-Methyl-2-thiophen-2-yl-4-oxazoleethanol

mp 71° C.; ¹H NMR (500 MHz, CDCl₃): δ 7.54 (m, 1H), 7.33 (m, 1H), 7.03(m, 1H), 3.87 (t, J=5.8 Hz, 2H), 3.5 (s, 1H), 2.67 (t, J=5.8 Hz, 2H),2.25 (s, 3H).

2-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethanol

¹H NMR (500 MHz, CDCl₃) δ 7.91 (d, 2H, J=8.60 Hz), 7.45-34 (m, 5H), 7.02(d, 2H, J=8.60 Hz), 5.11 (s, 2H), 3.91 (t, 2H, J=5.7 Hz), 2.71 (t, 2H,J=5.7 Hz), 2.31 (s, 3H); MS (ES⁺) Calc'd for C₁₉H₂₀NO₃: Found m/e 310(M+1, 100%)

Step E Toluene-4-sulfonic acid2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethyl ester

To a solution of 2-(4-bromophenyl)-5-methyl-4-oxazoleethanol

(8.89 g, 31.5 mmol) in CH₂Cl₂ (150 mL) at rt under N₂ was added pyridine(8.74 g, 110 mmol, 8.9 mL) and DMAP (0.97 g, 7.88 mmol) followed byportionwise addition of tosyl anhydride (12.7 g, 37.8 mmol). Thereaction exothermed to 32° C. and was stirred 1 h before 1N HCl (200 mL)was added. The mixture was stirred vigorously 15 min, and then theorganic phase was dried (MgSO₄) and filtered through a pad of silica gel(200 mL, packed with CH₂Cl₂). After rinsing the silica gel with EtOAc(100 mL) the solution was concentrated to toluene-4-sulfonic acid2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethyl ester which was usedwithout further purification (mp 136° C.).

Using the corresponding alcohols, the following compounds were preparedby the same procedure:

Toluene-4-sulfonic acid 2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethylester.

¹H NMR (300 MHz, CDCl₃) δ 7.99 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.64 (d,J=8.0 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.20 (d,J=9.0 Hz, 1H), 4.30 (t, J=7.0 Hz, 2H), 2.80 (t, J=7.0 Hz, 2H), 2.30 (s,3H), 2.23 (s, 3H). Toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethyl ester.

mp 107-109° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J=8.3 Hz, 2H), 7.51(dd, J=3.8, 1.4 Hz, 1H), 7.37 (dd, J=4.9, 1.2 Hz, 1H), 7.21 (d, J=7.9Hz, 2H), 7.08 (dd, J=4.8, 3.5 Hz, 1H), 4.28 (t, J=6.3 Hz, 2H), 2.80 (t,J=6.3 Hz, 2H), 2.28 (s, 3H), 2.26 (s, 3H).

Toluene-4-sulfonic acid2-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester. ¹H NMR (500MHz, CDCl₃) δ 7.80-7.78 (m, 2H), 7.67-7.65 (m, 2H), 7.45-7.34 (m, 5H),7.25-7.17 (m, 2H), 7.02-6.99 (m, 2H), 5.12 (s, 2H), 4.29 (t, 2H, J=6.45Hz), 2.80 (t, 2H, J=6.45 Hz), 2.27 (s, 3H), 2.22 (s, 3H); ¹³C (125 MHz,CDCl₃) δ 160.25, 144.8, 144.6, 136.5, 132.8, 130.6, 130.2, 129.6, 128.6,128.1, 127.8, 127.6, 127.4, 127.0, 115.1, 70.1, 68.9, 25.9, 21.4, 10.0;IR (KBr) 1645, 1613, 1499, 1351, 1248, 1190, 1173, 900, 665, 556 cm⁻¹;UV (EtOH) λ_(max) 286 nm (e 22658); HRMS (ES⁺) m/z exact mass calcd forC₂₆H₂₆NO₅S 464.1532, found 464.1531; Anal. Calc'd for C₂₆H₂₅NO₅S: C,67.37; H, 5.44; N, 3.02. Found C, 66.59; H, 5.33; N, 3.06

Step F2-(4-{2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester

A mixture of toluene-4-sulfonic acid2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethyl ester (prepared asdescribed in E above), 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethylester (American Home Products U.S. Pat. No 3,795,691) (7.06 g, 31.5mmol) and Cs₂CO₃ (13.3 g, 41.0 mmol) was heated at 55° C. in DMF (45 mL)for 18 h. The reaction was partitioned between EtOAc (250 mL) and H₂O(250 mL), and the aqueous phase extracted with EtOAc (2×100 mL). Thecombined organic phases were dried (MgSO₄) and concentrated underreduced pressure to an oil which was purified by column chromatography(1500 mL SiO₂, hexanes to 10% EtOAc/hexanes) to provide2-(4-(2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy)phenoxy)-2-methylpropionic acid ethyl ester (6.81 g, 44%) as a off-white solid: Rf=0.48in 35% EtOAc/hexanes; mp 78-79° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.85-7.82(m, 2H), 7.57-7.53 (m, 2H), 6.83-6.75 (m, 4H), 4.22 (q, J=7.0 Hz, 2H),4.18 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.7 Hz, 2H), 2.36 (s, 3H), 1.52 (s,6H), 1.27 (t, J=7.0 Hz, 3H) and by-product2-(4-Bromophenyl)-5-methyl-4-vinyloxazole (1.81 g, 22%) as a whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 7.92-7.87 (m, 2H), 7.58-7.55 (m, 2H),6.54 (dd, J=17.3, 10.8 Hz, 1H), 5.94 (dd, J=17.0, 1.8 Hz, 1H), 5.30 (dd,J=10.8, 1.8 Hz, 1H), 2.41 (s, 3H).

The following compounds were prepared by the same procedure usingtoluene-4-sulfonic acid 2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethylester and toluene-4-sulfonic acid2-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester,respectively:

2-(4-{2-[2-(3-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionicacid ethyl ester

Rf=0.39 in 1:4 EtOAc:hexanes; ¹H MMR (400 MHz, CDCl₃) δ 8.11 (t, J=1.6Hz, 1H), 7.89-7.86 (m, 1H), 7.49 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.27 (t,J=8.0 Hz, 1H), 6.80-6.72 (m, 4H), 4.20 (q, J=7.2 Hz, 2H), 4.15 (t, J=6.6Hz, 2H), 2.92 (t, J=6.6 Hz, 2H), 2.34 (s, 3H), 1.49 (S, 6H), 1.24 (t,J=7.2 Hz, 3H); MS (EI) 510.1 (M+Na)⁺, 488.1 (M+H)⁻.

2-Methyl-2-(4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenoxyapropionicacid ethyl ester. MS (ES) m/e 416.2 (M+1).

2-(4-{2-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester

¹H NMR (500 MHz, CDCl₃) δ 7.91 (d, 2H, J=8.60 Hz), 7.45-7.33 (m, 5H),7.01 (d, 2H, J=9.0 Hz), 6.83-6.69 (m, 4H), 5.10 (s, 2H), 4.25-4.09 (m,4H), 2.94 (t, 2H, J=6.65 Hz), 2.34 (s, 3H), 1.52 (s, 6H), 1.29 (t, 3H,J=9.2 Hz); ¹³C (125 MHz, CDCl₃) δ 174.3, 160.3, 159.5, 154.4, 148.9,144.5, 136.5, 132.1, 128.6, 128.1, 127.7, 127.5, 121.9, 121.6, 115.7,115.1, 114.9, 79.7, 70.1, 67.0, 61.2, 26.3, 25.3, 14.1, 10.1; IR (KBr)2987, 2874, 1729, 1614, 1505, 1287, 1245, 1228, 1171, 1142, 1022, 838cm⁻¹; UV (EtOH) λ_(max) 286 nm (ε 24476); HRMS (ES⁺) m/z exact masscalcd for C₃₁H₃₄NO₆ 516.2386, found 516.2362; Anal. Calc'd forC₃₁H₃₃NO₆: C, 72.21; H, 6.45; N, 2.71. Found C, 71.90; H, 6.62; N, 2.51

Step G2-(4-{2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

2-(4-{2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester was hydrolyzed as described in Example 1 to providedthe product: ¹H NMR (300 MHz, CDCl₃) δ 7.85-7.82 (m, 2H), 7.57-7.53 (m,2H), 6.83-6.75 (m, 4H), 4.18 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.7 Hz, 2H),2.36 (s, 3H), 1.52 (s, 6H)

The following compounds were hydrolyzed by the same procedure:

Example 9A2-(4-{2-[2-(3-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

mp 158-159° C.; Rf=0.1 in 6:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ8.10 (s, 1H), 7.88 (d, 1H), 7.47 (d, 1H) 7.31 (t, 1H), 6.86-6.76 (m,4H), 4.17 (t, 2H), 2.97 (t, 2H), 2.35 (s, 3H), 1.46 (s, 6H); MS (EI)461.0 (M+H)⁺.

Example 9B2-(4-[2-{2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.94 (d, 2H, J=7.82 Hz), 7.44-7.34 (m, 5H),7.01 (d, 2H, J=8.60 Hz), 6.90-6.84 (m, 2H), 6.80-6.74 (m, 2H), 5.10 (s,2H), 4.19 (t, 2H, J=6.65 Hz), 2.934 (t, 2H, J=6.65 Hz), 2.37 (s, 3H),1.52 (s, 6H); HRMS (ES⁺) m/z exact mass calcd for C₂₉H₃₀NO₆ 488.2073,found 488.2058.

Example 102-(4-{2-[2-(3-Ethynylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

Step A2-(4-{2-[2-(3-Ethynylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester

A solution of2-(4-{2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethoxy}-phenoxy)-2-methylpropionicacid ethyl ester (780 mg, 1.6 mmol), tributyl-(ethynyl)stannane (1.02 g,3.2 mmol, 0.934 mL), and Pd(PPh₃)₄ (92 mg, 0.08 mmol) in THF (80 mL) washeated at reflux for 18 h. The reaction mixture was cooled to rt,concentrated to a dark green paste, and filtered through a plug ofsilica gel (50 g, 1:4 EtOAc:hexanes). The material was further purifiedby two iterations of column chromatography (40 g SiO₂, 1:4EtOAc:hexanes) to provide the product (550.6 mg, 79%) as a faintly greenoil: Rf=0.30 in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s,1H), 7.92 (d, 1H), 7.44 (d, 1H), 7.36 (t, 1H), 6.81-6.72 (m, 4H),4.22-4.12 (m, 4H), 3.09 (s, 1H), 2.91 (t, 2H), 2.32 (s, 3H), 1.44 (s,6H), 1.22 (t, 3H); MS (EI) 456.2 (M+Na)⁺, 434.2 (M+H)⁺.

Using tributyl(vinyl)tin and tributyl(phenylethynyl)tin, respectively,the following compounds were prepared by the same procedure:

2-Methyl-2-(4-{2-[5-methyl-2-(3-vinylphenyl)oxazol-4-yl]ethoxy}phenoxy)propionicacid ethyl ester

Rf=0.29 in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H),7.85-7.81 (ma, 1H), 7.50-7.34 (m, 3H), 6.80-6.69 (m, 4H), 5.82 (d, 1H),5.28 (d, 1H), 4.22-4.10 (m, 4H), 2.92 (t, 2H), 2.33 (s, 3H), 1.44 (s,6H), 1.24 (t, 3H); MS (EI) 436.2 (M+H)⁺.

2-Methyl-2-(4-{2-[5-methyl-2-(3-phenylethynylphenyl)oxazol-4-yl]ethoxy}phenoxy) propionic acid ethyl ester

Rf=0.46 in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H),7.90 (d, 1H), 7.53-7.49 (m, 3H), 7.40-7.28 (m, 4H), 6.81-6.72 (m, 4H),4.21-4.14 (m, 4H), 2.93 (t, 2H), 2.32 (s, 3H), 1.48 (s, 6H), 1.23 (t,3H); MS (EI) 532.2 (M+Na)⁺, 510.2 (M+H)⁺.

Step B2-(4-{2-[2-(3-Ethynylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid

2-(4-{2-[2-(3-Ethynylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (94.7 mg, 0.218 mmol) was hydrolyzedaccording to the procedure in Example 2, Step D to provide the product(67.2 mg, 76%) as a white solid: Rf=0.10 in 6:4 EtOAc:hexanes;mp=131-134° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.93 (d, 1H),7.44 (d, 1H), 7.36 (t, 1H), 6.83-6.74 (m, 4H), 4.18 (t, 2H), 3.07 (s,1H), 2.96 (t, 2H), 2.35 (s, 3H), 1.46 (s, 6H); MS (EI) 428.1 (M+Na)⁺,406.2 (M+H)⁺.

The corresponding esters were hydrolyzed according to the aforementionedprocedure:

Example 10A2-Methyl-2-(4-{2-[5-methyl-2-(3-vinylphenyl)oxazol-4-yl]ethoxy}phenoxy)propionic acid

Rf=0.19 in 6:4 EtOAc:hexanes; mp=137-139° C.; ¹H NMR (400 MHz, CDCl₃) δ7.98 (s, 1H), 7.86-7.80 (m, 1H), 7.46-7.38 m, 3H), 6.88-6.77 (m, 4H),5.82 (d, 1H), 5.24 (d, 1H), 4.18 (t, 2H), 2.96 (t, 2H), 2.38 (s, 3H),1.42 (s, 6H); MS (EI) 430.2 (M+Na)⁺, 408.2 (M+H)⁺.

Example 10B2-Methyl-2-(4-{2-[5-methyl-2-(3-phenylethynylphenyl)oxazol-4-yl]ethoxy}phenoxy)propionic acid

Rf=0.15 in 6:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H),7.90 (d, J=8.0 Hz, 1H), 7.55-7.43 (m, 3H), 7.39 (t, J=8.0 Hz, 1H),7.35-7.31 (m, 3H), 6.89-6.76 (m, 4H), 4.15 (t, J=6.6 Hz, 2H), 2.96 (t,J=6.6 Hz, 2H), 2.36 (s, 3H), 1.49 (s, 6H); MS (EI) 504.1 (M+Na)⁺, 482.1(M+H)⁺.

Example 112-(4-{2-[2-(4-Ethynylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

Step A2-(4-{2-[2-(4-Ethynylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester

2-(4-{2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionicacid ethyl ester (298 mg, 0.610 mmol) was coupled withtributyl(ethynyl)stannane according to the procedure in Example 10 StepA, to provide the product (224.6 mg, 49%) as an off-white solid: Rf=0.43in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, 2H), 7.43 (d,2H), 6.80-6.68 (m, 4H), 4.20-4.11 (m, 4H), 3.12 (s, 1H), 2.88 (t, 2H),2.32 (s, 3H), 2.46 (s, 6H), 1.21 (t, 3H); MS (EI) 456.2 (M+Na)⁺, 434.2(M+H)⁴.

The following compound was prepared by the same procedure, usingtributyl(phenylethynyl)stannane:

2-Methyl-2-(4-{2-[5-methyl-2-(4-phenylethynylphenyl)-oxazol-4-yl]ethoxy}-phenoxy)propionicacid ethyl ester

Rf=0.38 in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, 2H),7.56 (d, 2H) 7.48, (m, 2H), 7.33-7.32 (m, 3H) 6.81-6.74 (m, 4H),4.21-4.15 (m, 4H), 2.93 (t, 2H), 2.34 (s, 3H), 1.53 (s, 6H), 1.24 (t,3H); MS (EI) 532.2 (M+Na)⁺, 510.2 (M+H)⁺.

Step B2-(4-{2-[2-(4-Ethynylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

2-(4-{2-[2-(4-Ethynylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionicacid ethyl ester (53.2 mg, 0.123 mmol) was hydrolyzed according to theprocedure in Example 2, Step D to provide the product (31.7 mg, 64%) asa white solid: Rf=0.11 in 6:4 EtOAc:hexanes; mp=137-139° C.; ¹H NMR (400MHz, CDCl₃) δ 7.92 (d, 2H), 7.50 (d, 2H), 6.86-6.78 (m, 4H), 4.17 (t,2H), 3.18 (s, 1H), 2.97 (t, 2H), 2.37 (s, 6H), 1.51 (s, 6H); MS (EI)428.1 (M+Na)⁺, 406.1 (M+H)⁺.

The following compound was prepared by the same procedure:

Example 11A2-Methyl-2-(4-{2-[5-methyl-2-(4-phenylethynylphenyl)oxazol-4-yl]ethoxy}-phenoxy)propionicacid

Rf=0.12 in 6:4 EtOAc:hexanes; MS (EI) 504.2 (M+Na)⁺, 482.2 (M+H)⁺.

Example 122-(4-{2-[2-(3-Ethylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

Step A2-(4-{2-[2-(3-Ethylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester

In a 250 mL thick-walled flask, a magnetically stirred solution of2-(4-{2-[2-(3-ethynylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester (4.72 g, 10.9 mmol) in EtOH:EtOAc (136 mL of a 9:1solution) was purged with nitrogen (3×), then treated with 10% Pd/C (630mg, 0.592 mmol Pd). The mixture was purged with H₂ (3×), followed byapplication of H₂ at 50 p.s.i. for 14 h. After a subsequent nitrogenpurge (3×), the mixture was filtered through celite and concentrated toan oil, which was purified by column chromatography (350 g SiO₂, 1:9EtOAc:hexanes to 1:4 EtOAc:hexanes) to provide the product (3.36 g, 70%)as a colorless oil: Rf=0.34 in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz,CDCl₃) δ 7.81 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H),7.21 (d, J=7.6 Hz, 1H), 6.80-6.73 (m, 4H), 4.20 (q, J=6.8 Hz, 2H), 4.16(t, J=6.4 Hz, 2H), 2.93 (t, J=6.4 Hz, 2H), 2.67 (q, j=7.2 Hz, 2H), 2.34(s, 3H), 1.49 (s, 6H), 1.26-1.23 (m, 6H); MS (EI) 460.2 (M+Na)⁺, 438.2(M+H)⁺.

The following compound was prepared by the same procedure, using2-methyl-2-(4-{2-[5-methyl-2-(3-phenylethynylphenyl)oxazol-4-yl]ethoxy}phenoxy)propionicacid ethyl ester:

2-Methyl-2-(4-{2-[5-methyl-2-(3-phenethylphenyl)oxazol-4-yl]ethoxy}phenoxy)-propionicacid ethyl ester

Rf=0.36 in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H),7.79 (d, 1H), 7.32-7.20 (m, 3H), 7.19-7.13 (m, 4H), 6.80-6.72 (m, 4H),4.23-4.16 (m, 4H), 2.94-2.86 (m, 6H), 2.34 (s, 3H), 1.43 (s, 6H),1.24-1.19 (m, 6H); MS (EI) 536.2 (M+Na)⁺, 514.2 (M+H)⁺.

Step B2-(4-{2-[2-(3-Ethylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

2-(4-{2-[2-(3-Ethylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionicacid ethyl ester (3.36 g, 7.86 mmol) was hydrolyzed according to theprocedure in Example 2, Step D to provide the product (2.78 g, 89%) as awhite solid: Rf=0.12 in 6:4 EtOAc:hexanes; mp=134-135° C.; ¹H NMR (400MHz, CDCl₃) δ 7.83 (s, 1H), 7.78 (d, J=8 Hz, 1H), 7.32 (t, J=8 Hz, 1H),7.25 (d, J=8 Hz, 1H), 6.88-6.77 (m, 4H), 4.18 (t, J=6.8 Hz, 2H), 2.97(t, J=6.8 Hz, 2H), 2.67 (q, J=8 Hz, 0.2H), 2.36 (s, 3H), 1.49 (s, 6H)1.24 (t, J=8 Hz, 3H); MS (EI) 432.1 (M+Na)⁺, 410.1 (M+H)⁺.

The following compound was prepared according to the same procedure:

Example 12A2-Methyl-2-(4-{2-[5-methyl-2-(3-phenethylphenyl)oxazol-4-yl]ethoxy}phenoxy)-propionicacid

Rf=0.2 in 6:4 EtOAc:hexanes; mp=124-125° C.; ¹H NMR (400 MHz, CDCl₃) δ7.83 (s, 1H), 7.98 (d, 1H), 7.32-7.21 (m, 3H), 7.20-7.16 (m, 4H),6.88-6.76 (m, 4H), 4.16 (t, 2H), 2.99 (t, 2H), 2.92 (m, 4H), 2.36 (s,3H), 1.51 (s, 6H); MS (EI) 508.2 (M+Na)⁺, 486.3 (M+H)⁺.

Example 132-(4-(2-[2-(4-Ethylphenyl)-5-methyloxazol-4-yl]ethoxy)phenoxy)-2-methylpropionicacid

Step A2-(4-[2-[2-(4-Ethylphenyl)-5-methyloxazol-4-yl]ethoxyphenoxy)-2-methylpropionicacid ethyl ester

2-(4-{2-[2-(4-Ethynylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester was hydrogenated according to the procedurein Example 12, Step A to provide the product (196 mg, 87%) as acolorless oil: Rf=0.35 in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ7.83 (d, 2H), 7.21 (d, 2H), 6.80-6.74 (m, 4H), 4.22-4.18 (m, 4H), 2.93(t, 2H), 2.63 (q, 2H), 2.32 (s, 3H), 1.48 (s, 6H), 1.24-1.19 (m, 6H); MS(EI) 460.2 (M+Na)⁺, 438.2 (M+H)⁺.

By the same procedure, the following compound was prepared from2-methyl-2-(4-{2-[5-methyl-2-(4-phenylethynylphenyl)-oxazol-4-yl]ethoxy}phenoxy)propionicacid ethyl ester:

2-Methyl-2-(4-{2-[5-methyl-2-(4-phenethylphenyl)oxazol-4-yl]ethoxy}phenoxy)-propionicacid ethyl ester

Rf=0.38 in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, 2H),7.24-7.16 (m, 7H), 6.82-6.74 (m, 4H), 4.22-4.16 (m, 4H), 2.95-2.86 (m,6H), 2.31 (s, 3H), 1.50 (s, 6H), 1.24-1.20 (m, 6H); MS (EI) 536.2(M+Na)⁺, 514.2 (M+H)⁺.

Step B

2-(4-{2-[2-(4-Ethylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionicacid ethyl ester (196 mg, 0.449 mmol) was hydrolyzed according to theprocedure in Example 2, Step D to provide the product (162 mg, 88%) as awhite solid: Rf=0.08 in 6:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ8.23 (d, 2H), 7.22 (d, 2H), 6.84-6.70 (m, 4H), 4.18 (t, 2H), 2.98 (t,1H), 2.64 (t, 2H), 2.36 (s, 3H), 1.52 (s, 6H), 1.22 (t, 3H); MS (EI)432.2 (M+Na)⁺, 410.2 (M+H)⁺.

The following compound was prepared according to the same procedure:

Example 13A2-Methyl-2-(4-{2-[5-methyl-2-(4-phenethylphenyl)oxazol-4-yl]ethoxy}phenoxy)-propionicacid

Rf=0.18 in 6:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, 2H),7.22-7.10 (m, 7H), 6.88-6.78 (m, 4H), 4.18 (t, 2H), 2.99 (t, 2H), 2.92(m, 4H), 2.38 (s, 3H), 1.47 (s, 6H); MS (EI) 508.2 (M+Na)⁺, 486.2(M+H)⁺.

Example 142-(4-{2-[2-(4-Carbamoylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

Step A2-(4-{2-[2-(4-Cyanophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester

2-(4-{2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester (170 mg, 0.35 mmol), copper (I) cyanide (96 mg, 1.07mmol), and copper (I) iodide (120 mg, 0.63 mmol) were dissolved indimethylformamide (1.5 mL) and heated to 150° C. for 20 h. The mixturewas cooled ambient temperature and partitioned between EtOAc (20 mL) andsaturated aqueous FeCl₃ (20 mL). The organic phase was washed with FeCl₃solution, H₂O, brine and then dried (MgSO₄), filtered and concentrated.The product was purified by flash chromatography (15 mL SiO₂, 40%EtOAc/hexanes) and obtained as a clear, colorless oil (132 mg, 87%).Rf=0.32 in 35% EtOAc/hexanes; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=8.4Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 6.81-6.76 (m, 4H), 4.21 (q, J=6.4 Hz,2H), 4.18 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.38 (s, 3H), 1.51(s, 6H), 1.26 (t, J=7.2 Hz, 3H); MS (EI) 457.2 (M+Na)⁺; 435.2 (M+H)⁺.

Step B2-(4-{2-[2-(4-Carbamoylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester

2-(4-{2-[2-(4-Cyanophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester (60 mg, 0.14 mmol) and potassium carbonate (30 mg,excess) were dissolved in dimethylsulfoxide (1 mL). After cooling to 0°C., the mixture was treated with hydrogen peroxide (120·L of a 30%aqueous solution) and then warmed to ambient temperature. After stirringfor 1 h, the mixture was partitioned between EtOAc (15 mL) and H₂O. Theaqueous phase was extracted with EtOAc (3×), and then the combinedorganic phases were dried (MgSO₄), filtered and concentrated to providethe product as a white solid (58 mg, 93%): mp 112° C.; ¹H NMR (400 MHz,CDCl₃) δ 8.05 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 6.81-6.77 (m,4H), 6.12 (br s, 1H), 5.66 (br s, 1H), 4.22 (q, J=6.8 Hz, 2H), 4.18 (t,J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.38 (s, 3H), 1.52 (s, 6H), 1.27(t, J=7.2 Hz, 3H); MS (EI) 475.2 (M+Na)⁺, 453.2 (M+H)⁺.

Step C

2-(4-{2-[2-(4-Carbamoylphenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester was hydrolyzed was described in Example 1 to providethe product as a white solid (42 mg, 90%): Rf=0.7 in 100% EtOAc; mp126-127° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (br s, 1H), 7.93 (m, 4H),7.42 (br s, 1H), 6.77 (m, 4H), 4.10 (t, J=6.4 Hz, 2H), 2.86 (t, J=6.4Hz, 2H), 2.32 (s, 3H), 1.37 (s, 6H); MS (EI) 448.2 (M+Na)⁺, 425.1(M+H)⁺.

Example 152-(4-{2-[2-(4-Cyanophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid

2-(4-{2-[2-(4-Cyanophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester (prepared as described in Example 14) was hydrolyzedaccording to the procedure in Example 1 to provide the product as awhite solid: ¹H NMR (400 MHz, d₆-DMSO) δ 7.98 (d, J=8.0 Hz, 1H), 7.89(d, J=8.0 Hz, 1H), 6.75-6.74 (m, 4H), 4.09 (t, J=6.4 Hz, 2H), 2.86 (t,J=6.4 Hz, 2H), 2.31 (s, 3H), 1.34 (s, 6H); MS (EI) 407 (M+H)⁴.

Example 162-Methyl-2-(4-{2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionicacid

A mixture of2-(4-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester

(0.30 g, 0.614 mmol), potassium phosphate (0.26 g, 1.22 mmol),2-(di-tert-butylphosphino)biphenyl (0.014 g, 0.0469 mmol) and phenol(0.069 g, 0.733 mmol) in toluene (6 mL) was degassed three times bysuccessive application of vacuum to the reaction vessel followed bynitrogen purge. Palladium (II) acetate (0.007 g, 0.0312 mmol) was addedto the reaction and the mixture heated to reflux under nitrogen for 3 h.The reaction was cooled to room temperature, diluted with Et₂C, andextracted with water then 1 N NaOH (10 mL). The organic layer was dried(MgSO₄) and the solvent removed in vacuo to give 0.316 g of crude2-methyl-2-(4-{2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionicacid ethyl ester.

MS (ES⁺) Calc'd for C₃₀H₃₁NO₆: Found m/e 502.3 (M+1, 100%).

The crude2-methyl-2-(4-{2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionicacid ethyl ester (0.316 g, 0.614 mmol) was combined with 5 N NaOH (0.61mL, 3.05 mmol) in absolute EtOH (20 mL) and heated to reflux for 3 h.The reaction mixture was cooled, filtered through hyflo, and the solventremoved in vacuo from the filtrate. The residue was acidified with 1 NHCl (3.2 mL) and then extracted with EtOAc and water. The organic layerwas dried (MgSO₄) and the solvent removed in vacuo to give 0.282 g ofcrude2-methyl-2-(4-{2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethoxy})-phenoxy)-propionicacid. Approximately ⅓ of this material was purified by LCMS to afford0.014 g of analytically pure2-methyl-2-(4-{2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionicacid: ¹H NMR (500 MHz, CDCl₃) δ 7.90 (d, 2H, J=8.80 Hz), 7.36-7.32 (m,2H), 7.18-7.12 (m, 1H), 7.03-6.99 (m, 3H), 6.88-6.86 (m, 2H), 6.79-6.77(m, 3H), 4.16 (t, 2H, J=6.84 Hz), 2.94 (t, 2H, J=6.84 Hz), 2.34 (s, 3H),1.44 (s, 6H). HRMS (ES⁺) m/z exact mass calcd for C₂₆H₂₈NO₆ 474.1917,found 474.1929.

The following compounds were prepared by the same procedure using4-methoxyphenol, 4-hydroxybenzotrifluoride, o-cresol, guaiacol,3-tert-butylphenol, and 3-methoxyphenol, respectively:

Example 16A2-[4-(2-{2-[4-(4-Methoxy-phenoxy)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenoxy]-2-methyl-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.92 (d, 2H, J=8.80 Hz), 7.00-6.96 (m, 4H),6.91-6.85 (m, 4H), 6.77 (d, 2H, J=8.80 Hz), 4.17 (t, 2H, J=5.87 Hz),3.80 (s, 3H), 3.04 (t, 2H, J=5.87 Hz), 2.40 (s, 3H), 1.47 (s, 6H). HRMS(ES⁺) m/z exact mass calcd for C₂₉H₃₀NO₇ 504.2022, found 504.2046.

Example 16B2-Methyl-2-[4-(2-{5-methyl-2-[4-(4-trifluoromethyl-phenoxy)-phenyl]-oxazol-4-yl}-ethoxy)-phenoxy]-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.98 (d, 2H, J=8.80 Hz), 7.61 (d, 2H, J=8.80Hz), 7.11-7.08 (m, 4H), 6.87-6.86 (m, 2H), 6.78-6.75 (m, 2H), 4.17 (t,2H, J=5.87 Hz), 3.04 (t, 2H, J=5.87 Hz), 2.41 (s, 3H), 1.48 (s, 6H).HRMS (ES⁺) m/z exact mass calcd for C₂₉H₂₇NO₆F₃ 542.1790, found542.1806.

Example 16C2-Methyl-2-(4-{2-[5-methyl-2-(4-o-tolyloxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.84 (d, 2H, J=8.80 Hz), 7.21-7.04 (m, 3H),6.90-6.80 (m, 5H), 6.72-6.70 (m, 2H), 4.09 (t, 2H, J=6.60 Hz), 2.90 (t,2H, J=6.60 Hz), 2.29 (s, 3H), 2.14 (s, 3H), 1.45 (s, 6H). HRMS (ES⁺) m/zexact mass calcd for C₂₉H₃₀NO₆ 488.2073, found 488.2072.

Example 16D2-[4-(2-{2-[4-(2-Methoxy-phenoxy)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenoxy]-2-methyl-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.94 (d, 2H, J=9.0 Hz), 7.20-7.18 (m, 1H),7.07-6.85 (m, 5H), 6.87-6.85 (m, 2H), 6.77-6.75 (m, 2H), 4.17 (t, 2H,J=5.87 Hz), 3.76 (s, 3H), 3.06 (t, 2H, J=5.87 Hz), 2.41 (s, 3H), 1.48(s, 6H). HRMS (ES⁺) m/z exact mass calcd for C₂₉H₃₀NO₇ 504.2022, found504.2021.

Example 16E2-[4-(2-{9-[4-(3-tert-Butyl-phenoxy)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenoxy]-2-methyl-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.97 (d, 2H, J=8.60 Hz), 7.30-7.27 (m, 1H),7.23-7.18 (m, 1H), 7.08-7.02 (m, 3H), 6.88-6.82 (m, 3H), 6.78-6.75 (m,2H), 4.18 (t, 2H, J=5.87 Hz), 3.06 (t, 2H, J=5.87 Hz), 2.41 (s, 3H),1.48 (s, 6H), 1.29 (s, 9H). HRMS (ES⁺) m/z exact mass calcd forC₃₂H₃₆NO₆ 530.2543, found 530.2538.

Example 16F2-[4-(2-{2-[4-(3-Methoxy-phenoxy)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenoxy]-2-methyl-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.98 (d, 2H, J=9.0 Hz), 7.31-7.24 (m, 1H),7.08 (d, 2H, J=8.60 Hz), 6.89 (d, 2H, J=9.0 Hz), 6.79-6.77 (m, 3H),6.76-6.62 (m, 2H), 4.19 (t, 2H, J=5.87 Hz), 3.80 (s, 3H), 3.10 (t, 2H,J=5.87 Hz), 2.45 (s, 3H), 1.50 (s, 6H). HRMS (ES⁺) m/z exact mass calcdfor C₂₉H₃₀NO₇ 504.2022, found 504.2009.

Example 172-Methyl-2-(4-{2-[5-methyl-2-(3-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionicacid

Step A2-Methyl-2-(4-{2-[5-methyl-2-(3-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionicacid ethyl ester

A solution of2-(4-{2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionicacid ethyl ester

(303 mg, 0.620 mmol), phenol (116.7 mg, 1.24 mmol), potassium phosphate(276.4 mg, 1.302 mmol), palladium acetate (13.9 mg, 0.062 mmol), and2-(di-t-butylphosphino) biphenyl (27.8 mg, 0.093 mmol) were combinedunder N₂, to which toluene (6.2 mL) was added. The mixture was heated atreflux for 4 h. After cooling to rt, the mixture was partitioned betweenEt₂O (20 mL) and H₂O (10 mL). The layers were separated, and the organicphase was washed with 1M NaOH (10 mL), which was then dried over Na₂SO₄,and concentrated to a brown residue. The product was purified by silicagel chromatography (20 g SiO₂, 1:4 EtOAc:hexanes) to yield 104.9 mg(34%) as an oil. Rf=0.45 in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ7.98-7.96 (m, 1H), 7.74-7.71 (m, 1H), 7.63-7.62 (m, 1H), 7.43-7.33 (m,3H) 7.14-7.10 (m, 1H), 7.06-7.01 (m, 2H), 6.82-6.74 (m, 4H), 4.23 (q,J=8.0 Hz, 2H), 4.16 (t, J=6.4 Hz, 2H), 2.93 (t, J=6.4 Hz, 2H), 2.34 (s,3H), 1.52 (s, 6H), 1.28-1.24 (t, J=8.0 Hz, 3H); MS (EI) 540.0 (M+K)⁺,502.0 (M+H)⁺.

The following compound was prepared by the same procedure, using2-methylphenol:

2-Methyl-2-(4-{2-[5-methyl-2-(3-o-tolyloxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionicacid ethyl ester

Rf=0.45 in 1:4 EtOAc:hexanes; MS (EI) 554.1 (M+K)⁺, 516.1 (M+H).

Step B

2-Methyl-2-(4-{2-[5-methyl-2-(3-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionicacid2-Methyl-2-(4-{2-[5-methyl-2-(3-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)propionicacid ethyl ester (104.9 mg, 0.209 mmol) was hydrolyzed according to theprocedure in Example 2, Step D to provide the crude product, which waspurified by LC/MS to yield the product (3.8 mg, 3.8%) as a lyophilizedsolid. Rf=0.10 in 6:4 EtOAc:hexanes ¹H NMR (400 MHz, CDCl₃) δ 7.78-7.61(m, 1H), 7.69-7.66 (m, 1H), 7.42-7.29 (m, 3H), 7.13-6.97 (m, 3H),6.86-6.74 (m, 4H), 4.13 (t, J=6.2 Hz, 2H), 2.94 (s, J=6.2 Hz, 2H), 2.33(s, 3H), 1.46 (s, 6H); MS (EI) 474.1 (M+H)⁺.

The following compound was prepared by the same procedure, using2-Methyl-2-(4-{2-[5-methyl-2-(3-o-tolyloxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)propionicacid ethyl ester

Example 17A2-Methyl-2-(4-{2-[5-methyl-2-(3-o-tolyloxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionicacid

Rf=0.11 in 6:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ 7.63-7.62 (m,1H), 7.47-7.46 (m, 1H), 7.35-7:31 (m, 1H), 7.23 (s, 1H), 7.17-7.12 (m,1H) 7.07-7.03 (m, 1H) 6.94-6.82 (m, 4H), 6.75-6.72 (m, 2H) 4.11 (t,J=6.4 Hz, 2H), 2.96 (t, J=6.4 Hz, 2H), 2.33 (s, 3H), 2.19 (s, 3H), 1.47(s, 6H); MS (EI) 488.1 (M+H)⁺.

Example 182-[4-(2-{2-[4-(4-Benzoyl-phenoxy)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenoxy]-2-methyl-propionicacid

A mixture of2-(4-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester (0.20 g, 0.410 mmol), phenyl boronic acid (0.055 g,0.451 mmol), powdered K₂CO₃ (0.169 g, 1.22 mmol), potassium iodide (0.20g, 1.20 mmol), 1,1′-bis(diphenylphosphino) ferrocene (0.023 g, 0.0414mmol) and palladium (II) chloride (0.007 g, 0.0395 mmol) in anisole (4mL) and then carbon monoxide was bubbled through the reaction mixture tosaturate the mixture. The reaction was then heated at 80° C. in an oilbath under a carbon monoxide balloon for 2 h. The reaction was cooled,diluted with Et₂O, and extracted with water and brine. The organic layerwas dried (MgSO₄) and the solvent removed in vacuo to give an oil thatpassed over a plug of silica gel to remove most of the anisole (98:2ratio CH₂Cl₂:MeOH). The resultant oil was dissolved in EtOH (8 mL) andtreated with 5 N NaOH (0.1 mL) at reflux for 1 h. The reaction mixturewas cooled, acidified with 1 N HCl (1 mL) and the reaction mixtureextracted with EtOAc and water to give 0.061 g of crude2-[4-(2-{2-[4-(4-benzoyl-phenoxy)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenoxy)-2-methyl-propionicacid that was purified by LCMS to afford 0.017 g of2-[4-(2-(2-[4-(4-benzoyl-phenoxy)-phenyl]-5-methyl-oxazol-4-yl)-ethoxy)-phenoxy]-2-methyl-propionicacid.

¹H NMR (500 MHz, CDCl₃) δ 8.10 (d, 2H, J=8.21 Hz), 7.90 (d, 2H, J=8.21Hz), 7.80 (d, 2H, J=8.21 Hz), 7.63-7.60 (m, 1H), 7.53-7.49 (m, 2H), 6.90(d, 2H, J=9.0 Hz), 6.80 (d, 2H, J=8.60), 4.21 (t, 2H, J=5.87 Hz), 3.07(t, 2H, J=5.87 Hz), 2.45 (s, 3H), 1.52 (s, 6H). HRMS (ES⁺) m/z exactmass calcd for C₂₉H₂₈NO₆ 486.1117, found 486.1904.

Example 192-(4-{2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

Step A2-(4-{2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester

A mixture of2-(4-{2-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester (8.16 g, 15.8 mmol) and 5% palladium on carbon (1.63 g)in tetrahydrofuran (100 mL) and methanol (100 mL) was purgedsuccessively with nitrogen then hydrogen, and then stirred under ahydrogen balloon at room temperature for 18 h. The reaction mixture wasfiltered through hyflo and solvent was removed from the filtrate invacuo to give an oil which was dissolved in EtOAc and dried (MgSO₄). Thesolvent was removed in vacuo to afford 6.40 g (95%) of2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy)-phenoxy)-2-methyl-propionicacid ethyl ester. ¹H NMR (500 MHz, CDCl₃) δ 8.25 (bs, 1H), 7.32 (d, 2H,J=8.79 Hz), 6.75-6.67 (m, 4H), 6.65 (d, 2H, J=8.79 Hz), 4.17 (q, 2H,J=6.84 Hz), 4.09 (t, 2H, J=6.35 Hz), 9.88 (t, 2H, J=6.35 Hz), 2.30 (s,3H), 1.45 (s, 6H), 1.2-1 (t, 3H, J=6.84 Hz); ¹³C (125 MHz, CDCl₃) δ174.4, 160.2, 159.0, 154.3, 148.9, 144.7, 131.5, 128.1, 122.0, 121.6,118.7, 115.9, 115.7, 114.9, 79.8, 66.8, 61.3, 25.9, 25.2, 14.1, 10.1; IR(KBr) 2985, 2941, 2809, 2606, 1742, 1731, 1507, 1442, 1277, 1233, 1213,1170, 1137 cm¹; UV (EtOH) λ_(max) 285 nm (ε 21145), 219 nm (·15842);HRMS (ES⁺) m/z exact mass calcd for C₂₄H₂₈NO₆ 426.1917, found 426.1896;Anal. Calc'd for C₂₄H₂₇NO₆: C, 67.75; H, 6.40; N, 3.29. Found C, 67.22;H, 6.50; N, 2.79

Step B

2-(4-{2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

A mixture of2-(4-{2-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid (0.238 g, 0.490 mmol) and 5% palladium on carbon (0.10 g) intetrahydrofuran (10 mL) and methanol (10 mL) was purged successivelywith nitrogen then hydrogen, and then stirred under a hydrogen balloonat room temperature for 18 h. The reaction mixture was filtered throughhyflo and solvent was removed from the filtrate in vacuo to give an oilwhich was dissolved in CH₂Cl₂ and dried (MgSO₄). The solvent was removedin vacuo to give a crude oil which was purified by flash chromatography(9/1 CH₂Cl₂/MeOH) to afford 0.072 g (37%)2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid. ¹H NMR (500 MHz, DMSO-d₆) δ 10.08 (bs, 1H), 7.70 (d, 2H, J=8.60Hz), 6.84-6.72 (m, 6H), 4.08 (t, 2H, J=6.65 Hz), 2.83 (t, 2H, J=6.65Hz), 2.28 (s, 3H), 1.33 (s, 6H); MS (ES⁺) Calc'd for C₂₂H₂₃NO₆: Foundm/e 398 (M+1, 100%)

Example 202-(4-{2-[2-(4-Methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

Step A2-(4-{2-[2-(4-Methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester

A solution of2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester (0.15 g, 0.352 mmol), methyl iodide (0.15 g, 1.06mmol), tetrabutylammonium bromide (0.023 g, 0.0713) mmol) in CH₂Cl₂ (8mL) was treated with a 50% weight solution of NaOH (0.1 mL), and stirredat room temperature. The reaction mixture was extracted with water andmore CH₂Cl₂ and the organic layer dried (MgSO₄). The solvent was removedin vacuo to give a crude oil which was purified by flash chromatography(2/1 hexanes/EtOAc) to afford 0.038 g (25%)2-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester. ¹H NMR (500 MHz, CDCl₃) δ 7.87-7.85 (m, 2), 6.90-6.88(m, 2H), 6.78-6.71 (m, 4H), 4.21-4.06 (m, 4H), 3.80 (s, 3H), 2.88 (t,2H, J=6.60 Hz), 2.29 (s, 3H), 1.47 (s, 6H), 1.23 (t, 3H, J=7.33 Hz); MS(ES⁺) Calc'd for C₂₅H₃₀NO₆: Found m/e 440 (M+1, 100%).

Step B2-(4-{2-[2-(4-Methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

A solution of2-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy)-phenoxy)-2-methyl-propionicacid ethyl ester (0.036 g, 0.0819 mmol) in ethanol (5 mL) was treatedwith 5 N NaOH (0.1 mL) and the reaction heated to reflux for 1 h. Thereaction mixture was cooled and the solvent removed in vacuo. Theresultant oil was acidified with 1 N HCl and extracted with EtOAc andwater. The organic layer was dried (MgSO₄) and the solvent removed invacuo to afford 0.034 g (100%) of2-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy)-phenoxy)-2-methyl-propionicacid. ¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, 2H, J=8.60 Hz), 6.94 (d, 2H,J=8.60 Hz), 6.90-6.87 (m, 2H), 6.79-6.77 (m, 2H), 4.17 (t, 2H, J=6.45Hz), 3.85 (s, 3H), 2.98 (t, 2H, J=6.45 Hz), 2.36 (s, 3H), 1.52 (s, 6H);HRMS (ES⁺) m/z exact mass calcd for C₂₃H₂₆NO₆ 412.1760, found412.1783The following compounds were prepared following the sameprocedure using ethyl iodide, 2-iodopropane, 1-iodopropane, and1-iodohexane, respectively:

Example 20A2-(4-{2-[2-(4-Ethoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.90-7.88 (m, 2H), 6.93-6.88 (m, 4H),6.80-6.77 (m, 2H), 4.16 (t, 2H, J=6.65 Hz), 4.07 (q, 2H, J=6.65 Hz),2.96 (t, 2H, J=6.65 Hz), 2.35 (s, 3H), 1.52 (s, 6H), 1.43 (t, 3H, J=6.65Hz); HRMS (ES⁺) m/z exact mass calcd for C₂₄H₂₈NO₆ 426.1917, found426.1945

Example 20B2-(4-{2-[2-(4-Isopropoxyphenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.82-7.80 (m, 2H), 6.85-6.80 (m, 4H),6.71-6.69 (m, 2H), 4.53 (septet, 1H, J=6.25 Hz), 4.07 (t, 2H, J=6.65Hz), 2.89 (t, 2H, J=6.65 Hz), 2.28 (s, 3H), 1.46 (s, 6H), 1.28 (d, 6H,J=6.25 Hz); HRMS (ES⁺) m/z exact mass calcd for C₂₅H₃₀NO₆ 440.2073,found 440.2104

Example 20C2-Methyl-2-(4-{2-[5-methyl-2-(4-propoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.83-7.80 (m, 2H), 6.87-6.81 (m, 4H),6.73-6.71 (m, 2H), 4.09 (t, 2H, J=6.65 Hz), 3.89 (t, 2H, J=6.65 Hz),2.88 (t, 2H, J=6.65 Hz), 2.28 (s, 3H), 1.78-1.73 (m, 2H), 1.45 (s, 6H),0.98 (t, 3H, J=7.43 Hz), HRMS (ES⁺) m/z exact mass calcd for C₂₅H₃₀NO₆440.2073, found 440.2047

Example 20D2-(4-{2-[2-(4-Hexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.82 (d, 2H, J=8.21 Hz), 6.86-6.81 (m, 4H),6.71 (m, 2H, J=900 Hz), 4.09 (t, 2H, J=6.65 Hz), 3.92 (t, 2H, J=6.65Hz), 2.90 (t, 2H, J=6.65 Hz), 2.28 (s, 3H), 1.74-1.68 (m, 2H), 1.45 (s,6H), 1.43-1.35 (m, 2H), 1.33-1.25 (m, 4H), 0.88-0.71 (m, 3H); HRMS (ES⁺)m/z exact mass calcd for C₂₈H₃₆NO₆ 482.2543, found 482.2552

Example 212-(4-{2-[2-(4-Cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

Step A2-(4-{2-[2-(4-Cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester

To a 0° C. solution of2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester (0.60 g, 1.41 mmol), cyclohexanol (0.212 g, 2.11 mmol)and triphenyl phosphine (0.55 g, 2.10 mmol) in THF (18 mL) was addeddiisopropyl azodicarboxylate (0.43 g, 2.12 mmol) in THF (2 mL). Thereaction was warmed to room temperature and stirred under N₂ for 18 h.Silica gel was added directly to the reaction mixture and the solventremoved in vacuo to absorb the crude product onto the silica gel. Thecrude product was then purified by flash chromatography (3/1hexanes/EtOAc) to afford 0.339 g (47%)2-(4-{2-[2-(4-cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester. ¹H NMR (500 MHz, CDCl₃) δ 7.94-7.85 (m, 2H), 6.92 (d,2H, J=9.0 Hz), 6.82-6.75 (m, 4H), 4.32-4.23 (m, 1H), 4.21-4.16 (m, 4H),2.98-2.90 (m, 2H), 2.39 (s, 3H), 2.05-1.95 (m, 2H), 1.85-1.78 (m, 2H),1.62-1.51 (m, 3H), 1.52 (s, 6H), 1.42-1.25 (m, 3H), 1.27 (t, 3H, J=7.23Hz); MS (ES⁺) Calc'd for C₃₀H₃₈NO₆: Found m/e 508.3 (M+1, 100%).

Step B2-(4-{2-[2-(4-Cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

A solution of2-(4-{2-[2-(4-cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester (0.339 g, 0.667 mmol) in ethanol (40 mL) was treatedwith 5 N NaOH (0.8 mL) and the reaction heated to reflux for 1 h. Thereaction mixture was cooled and the solvent removed in vacuo. Theresultant oil was acidified with 1 N HCl and extracted with EtOAc andwater. The organic layer was dried (MgSO₄) and the solvent removed invacuo to afford 0.304 g (95%) of2-(4-{2-[2-(4-cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid. ¹H NMR (500 MHz, CDCl₃) δ 7.94-7.85 (m, 2H), 6.89-6.73 (m, 4H),6.71 (d, 2H, J=9.28 Hz), 4.30-4.23 (m, 1H), 4.14-4.05 (m, 2H), 2.95-2.85(m, 2H), 2.29 (s, 3H), 1.98-1.85 (m, 2H), 1.80-1.75 (m, 2H), 1.58-1.40(m, 8H), 1.38-1.20 (m, 4H); HRMS (ES⁺) m/z exact mass calcd forC₂₈H₃₄NO₆ 480.2386, found 480.2381 The following compound was preparedusing tetrahydro-2H-pyran-4-ol:

Example 21A2-Methyl-2-[4-(2-{5-methyl-2-[4-(tetrahydro-pyran-4-yloxy)-phenyl]-oxazol-4-yl}-ethoxy)-phenoxy]-propionicacid

¹H NMR (500 MHz, CDCl₃) δ 7.88-7.83 (m, 2H), 6.89 (d, 2H, J=8.79 Hz),6.84-6.80 (m, 2H), 6.79-6.72 (m, 2H), 4.51-4.46 (m, 1H), 4.12 (t, 2H,J=6.35 Hz), 3.94-3.89 (m, 2H), 3.56-3.50 (m, 2H), 2.92 (t, 2H, J=6.65Hz), 2.29 (s, 3H), 2.00-1.95 (m, 2H), 1.78-1.70 (m, 2H), 1.45 (s, 6H);HRMS (ES⁺) m/z exact mass calcd for C₂₇H₃₂NO₇ 482.2179, found 482.2189

Example 222-Methyl-2-[4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl)-ethoxy}-phenoxy]-propionicacid

Step A2-Methyl-2-[4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenoxy]-propionicacid ethyl ester

A flask charged with2-(4-{2-[2-(4-bromophenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester (3.00 g, 6.155 mmol), KOAc (1.81 g, 18.466 mmol), andbis(pinacolato)diboron (1.87 g, 7.387 mmol) in DMSO (31.2 mL) wasflushed and purged with N₂ three times.[1,1′-Bis(diphenylphosphino)-ferrocene]dichloro palladium(II), complexwith dichloromethane (1:1) (905 mg, 1.108 mmol) was then added. Afterbeing stirred at 80° C. for 2 h, the reaction was checked by HPLC. Theproduct was extracted with CH₂Cl₂ (60 mL) and washed with H₂O. Theaqueous layer was back extracted with CH₂Cl₂ (60 mL). The combinedorganic layers were washed with H₂O (50 mL), dried over NaCl, andsolvent removed in vacuo. Flash chromatography using hexanes, 10% EtOAc,20% EtOAc, then 40% EtOAc provided product in quantitative yield: ¹H NMR(400 MHz, CDCl₃) δ 7.94 (d, 2H), 7.82 (d, 2H), 6.76 (d, 2H), 6.73 (d,2H), 4.22 (q, 2H), 4.18 (t, 2H), 2.93 (t, 2H), 2.33 (s, 3H), 1.47 (s,6H), 1.31 (s, 12H), 1.21 (t, 3H); MS (EI) 536.3 (M+H)⁺.

Step B2-Methyl-2-[4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenoxy]-propionicacid

A sample of2-methyl-2-[4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenoxy]-propionicacid ethyl ester (55 mg, 0.103 mmol) was dissolved in 10 mL of EtOH with3 mL of 5 N NaOH. This mixture was allowed to stir at 60° C. for 1 h.The mixture was cooled to room temperature and then acidified to pH 2 bythe dropwise addition of 5 N HCl. This acidic mixture was diluted with10 mL of H₂O and then extracted with CH₂Cl₂ (2×25 mL). The organiclayers were combined, dried over NaCl, and solvent removed in vacuowhich provided 49 mg (94%) of desired acid: ¹H NMR (400 MHz, CDCl₃) δ8.32 (d, 2H), 7.95 (d, 2H), 6.82 (d, 2H), 6.74 (d, 2H), 4.35 (t, 2H),3.25 (t, 2H), 2.50 (s, 3H), 1.44 (s, 6H), 1.32 (s, 12H); MS (EI) 508.0(M+H)⁺.

Example 232-Methyl-2-{3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid

Step A Toluene-4-sulfonic acid2-(2-phenyl-4-yl-5-methyloxazol-4-yl)ethyl ester

2-phenyl-5-methyl-4-oxazoleethanol was converted to toluene-4-sulfonicacid 2-(2-phenyl-4-yl-5-methyloxazol-4-yl)ethyl ester following theprocedure described in Example 9, Step E (mp 132-134° C.)

Step B2-Methyl-2-{3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid ethyl ester

Toluene-4-sulfonic acid 2-(2-phenyl-4-yl-5-methyloxazol-4-yl)ethyl ester(382 mg, 1.07 mmol) and 2-(3-hydroxyphenoxy)-2-methylpropanoic acidethyl ester (Columbia University WO 9731530) (200 mg, 0.89 mmol) werecoupled following the procedure described in Example 1 to provide theproduct (276 mg, 76%) as a colorless oil: Rf=0.59 in 20% EtOAc/hexanes;¹H NMR (400 MHz, CDCl₃) δ 7.94 (m, 2H) 7.40-7.38 (m, 3H), 7.06 (t, J=8.0Hz), 6.51 (d, J=3.0 Hz, 1H), 6.41 (s, 1H), 6.36 (d, 8.0 Hz), 4.22-4.15(m, 4H), 2.93 (t, J=6.8 Hz, 2H), 2.34 (s, 3H), 1.55 (s, 6H), 1.21 (t,J=9.4 Hz, 3H); MS (EI) 410.1 (M+H)⁺.

Step C2-Methyl-2-{3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid

2-Methyl-2-{3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid ethyl ester (276 mg) was hydrolyzed following the procedure inExample 2 to provide the product (4.30 g, 99%) as a white solid: mp140-141° C.; Rf=0.11 in 60% EtOAc/hexanes; ¹H NMR (400 MHz, CDCl₃) δ7.95 (m, 2H), 7.43-7.41 (m, 3H), 7.14 (t, J=8.0 Hz, 1H), 6.71 (s, 1H),6.62 (d, J=8.0 Hz, 1H), 6.53 (d, J=8.0 Hz, 1H), 4.19 (t, J=7.4 Hz, 2H),2.91 (t, J=7.4 Hz, 2H), 2.35 (s, 3H), 1.58 (s, 6H); MS (EI) 381.9(M+H)⁺.

Example 242-Methyl-2-{2-methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid

Step A 2-(4-Benzyloxy-2-formylphenoxy)-2-methyl propionic acid ethylester

5-Benzyloxy-2-hydroxy-benzaldehyde (Kappe, T.; Witoszynskyj, T. Arch.Pharm., 1975, 308 (5), 339-346) (2.28 g, 10.0 mmol), ethylbromoisobutyrate (2.2 mL, 15 mmol), and cesium carbonate (3.26 g, 10.0mmol) in dry DMF (25 mL) were heated at 80° C. for 18 h. The reactionmixture was cooled and partitioned between water (30 mL) and ether (75mL). The organic layer was washed with brine (15 mL). The aqueous layerswere back-extracted with ethyl acetate (30 mL), and the organic layerwas washed with brine (20 mL). The combined organic layers were dried(Na₂SO₄) and concentrated to a brown oil. The crude product was purifiedby flash chromatography using hexanes:ethyl acetate (2.5:1) to give apale yellow solid (3.04 g, 89%): mp 65° C.; ¹H NMR (400 MHz, CDCl₃) δ1.24 (t, 3H, J=7.1 Hz), 1.62 (s, 6H), 4.23 (q, 9H, J=7.1 Hz), 6.81 (d,1H, J=8.8 Hz), 7.10 (dd, 1H, J=4.6, 9.0 Hz), 7.30-7.43 (m, 6H); MS (ES)m/e 343.1 [M+1]

Step B 2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethylester

2-Methyl-2-{2-methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid (9.00 g, 26.3 mmol) in ethanol (250 mL) was treated with 5% Pd/C(1.25 g) and hydrogen (60 psi, rt, overnight). Additional 5% Pd/C (1.25g) was added, and the reaction was continued for 6 h at 40° C. Themixture was filtered and concentrated to a tan oil (6.25 g). This oilcontained 9 mol % of2-(4-Hydroxy-2-hydroxymethyl-phenoxy)-2-methyl-propionic acid ethylester. ¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, 3H, J=7.3 Hz), 1.51 (s, 6H),2.14 (s, 3H), 4.24 (q, 2H, J=7.3 Hz), 5.68 (brs, 1H), 6.47 (dd, 1H,J=3.4, 8.8 Hz), 6.59 (d, 1H, J=8.3 Hz), 6.60 (brs, 1H).

Step C2-Methyl-2-{2-methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid ethyl ester

A mixture of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acidethyl ester (4.50 g, 18.9 mmol), toluene-4-sulfonic acid2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (Japan Tobacco Inc WO9518125) (8.43 g, 23.6 mmol), and Cs₂CO₃ (7.68 g, 23.6 mmol) was heatedat 55° C. in DMF (45 mL) for 20 h. Additional toluene-4-sulfonic acid2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (2.81 g, 7.86 mmol) andCs₂CO₃ (2.56 g, 7.86 mmol) were added, and the mixture was heated at 55°C. in DMF (45 mL) for 6 h. The reaction mixture cooled and partitionedbetween EtOAc (200 mL) and H₂O (100 mL). The organic layer was washedwith brine (50 mL). The aqueous layers were extracted further with EtOAc(200 mL). The combined organic layers were dried (Na₂SOI) andconcentrated. The crude product was purified by flash chromatographyusing hexanes:ethyl acetate (6:1 to 4:1) to give an oil (5.81 g, 73%):¹H NMR (400 MHz, CDCl₃) δ 1.27 (t, 3H, J=7.1 Hz), 1.51 (s, 6H), 2.18 (s,3H), 2.36 (s, 3H), 2.95 (t, 2H, J=6.6 Hz), 4.17 (t, 2H, J=6.6 Hz), 4.24(q, 2H, J=7.1 Hz), 6.57 (dd, 1H, J=2.9, 8.8 Hz), 6.65 (d, 1H, J=9.3 Hz),6.69 (d, 1H, J=2.9 Hz), 7.38-7.45 (m, 3H), 7.98-8.00 (m, 2H); MS (ES)m/e 424.2 [M+1].

Step D2-Methyl-2-{2-methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid

A solution of2-methyl-2-{2-methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionicacid ethyl ester (5.00 g, 11.8 mmol) in THF (30 mL) and MeOH (60 mL) wastreated with 5N aqueous NaOH (20 mL). The solution was heated at 55° C.for 1 h, cooled to ambient temperature, and concentrated in vacuo. Theresidue was treated with ice water (20 mL), acidified with 5N aqueousHCl (25 mL), and extracted with ethyl acetate (200 mL). The organiclayer was washed with brine (40 mL), dried (Na₂SO₄), and concentrated toa white solid (4.46 g, 96%): mp 117° C.; ¹H NMR (400 MHz, CDCl₃) δ 1.53(s, 6H), 2.19 (s, 3H), 2.38 (s, 3H), 2.98 (t, 2H, J=6.6 Hz), 4.15 (t,2H, J=6.6 Hz), 6.58 (dd, 1H, J=3.4, 8.8 Hz), 6.70 (d, 1H, J=29 Hz), 6.80(d, 1H, J=8.8 Hz), 7.38-7.45 (m, 3H), 7.97-8.00 (m, 2H); MS (FIA) m/e394.2 [M−1].

Example 25{2-Methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]phenoxy}acetic acid

Step A (4-Benzyloxy-2-formylphenoxy)acetic acid ethyl ester

(4-Benzyloxy-2-formylphenoxy)acetic acid ethyl ester was prepared fromethyl bromoacetate following the procedure described in Example 24, StepA. ¹H NMR (400 MHz, CDCl₃) δ 1.29 (t, 3H, J=7.1 Hz), 4.27 (q, OH, J=7.0Hz), 4.71 (s, 2H), 5.06 (s, 2H), 6.85 (d, 1H, J=9.3 Hz), 7.17 (dd, 2H,J=3.2, 9.0 Hz), 7.46-7.33 (m, 5H), 10.54 (s, 1H); MS (ES) m/e 315 (M+1).

Step B (4-Hydroxy-2-methylphenoxy)acetic acid ethyl ester

(4-Benzyloxy-2-formylphenoxy)acetic acid ethyl ester was debenzylatedfollowing the procedure described in Example 24, Step B. ¹H NMR (400MHz, CDCl₃) δ 1.28 (t, 3H, J=7.1 Hz), 2.24 (s, 3H), 4.25 (q, 2H, J=7.1Hz), 4.55 (s, 2H), 6.56 (dd, 1H, J=2.7, 8.5 Hz), 6.61 (d, 1H, J=8.3 Hz),6.65 (d, 2H, J=2.9 Hz).

Step C{2-Methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}acetic acidethyl ester

(4-Hydroxy-2-methylphenoxy)acetic acid ethyl ester andtoluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl esterwere coupled as described in Example 24, Step C. ¹H NMR (400 MHz, CDCl₃)δ 1.28 (t, 3H, J=7.0 Hz), 2.25 (s, 3H), 2.36 (s, 3H), 2.94 (t, 2H, J=6.8Hz), 4.17 (t, 2H, J=6.6 Hz), 4.23 (q, 2H, J=7.0 Hz), 4.55 (s, 2H), 6.65(s, 2H), 6.72 (s, 1H), 7.38-7.44 (m, 3H), 7.94-7.97 (m, 2H); MS (ES) m/e396.2 (M+1).

Step D{2-Methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)acetic acid

{2-Methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}acetic acidethyl ester was hydrolyzed as described in Example 24, Step D. mp 133°C.; ¹H NMR (300 MHz, CDCl₃) δ 2.24 (s, 3H), 2.39 (s, 3H), 3.00 (t, 2H,J=6.2), 4.16 (t, 2H, J=6.587), 4.58 (s, 2H), 6.60 (dd, 1H, J=2.9, 9.0),6.72 (d, 1H, J=8.8), 6.72 (d, 1H, J=2.9), 7.42-7.48 (m, 3H), 7.98-8.03(m, 2H); MS (FIA) m/e 368.2 (M+1).

Example 26{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]-2-propylphenoxy}acetic acid

Step A 4-Benzyloxy-2-propylphenol

2-Allyl-4-benzyloxyphenol (WO 9728137 A1 19970807, Adams, A. D. et al.)(5.00 g, 20.8 mmol) in ethyl acetate (40 mL) was treated with 5% Pd/C(0.25 g) and hydrogen (1 atm) at ambient temperature for 18 h. Themixture was filtered and concentrated. The crude product was purified ona Biotage medium pressure chromatography system using a 40L normal phasecartridge and eluted with 10% ethyl acetate in hexanes to give a tansolid (2.8 g, 56%). Rf=0.33 (25% EtOAc/Hexanes); ¹H NMR (400 MHz, CDCl₃)δ 7.44-7.31 (m, 5H), 6.78 (s, 1H), 6.69 (d, J=1.5 Hz, 2H), 5.00 (s, 2H),4.31 (s, 1H), 2.55 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H), 0.97 (t,J=7.3 Hz, 3H).

Step B (4-Benzyloxy-2-propylphenoxy)acetic acid ethyl ester

A solution of 4-benzyloxy-2-propylphenol (0.50 g, 1.94 mmol) in dry DMF(7 mL) was cooled in an ice bath and treated with NaH (0.15 g, 3.8 mmol,60% oil dispersion). The ice bath was removed, ethyl bromoacetate (0.43mL, 3.9 mmol) was added, and the mixture was placed in an oil bath(T=85° C.). After 18 h, the reaction mixture was cooled and concentratedin vacuo. The residue was diluted with EtOAc, washed with brine (2×),dried (Na₂SO₄), and concentrated. The crude product was purified byradial chromatography using 10% ethyl acetate in hexanes to give a tansolid (0.62 g, 97%). ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.31 (m, 5H), 6.82(d, J=2.9 Hz, 1H), 6.72 (dd, J=8.8, 2.9 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H),5.00 (s, 2H), 4.57 (s, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.63 (t, J=7.6 Hz,2H), 1.64 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz,3H); MS (FIA) m/e 329 (M+1).

Step C (4-Hydroxy-2-propylphenoxy)acetic acid ethyl ester

A solution of (4-benzyloxy-2-propylphenoxy)acetic acid ethyl ester (0.60g, 1.83 mmol) in THF (15 mL) was treated with 5% Pd/C (75 mg) andhydrogen (60 psi) at ambient temperature for 24 h. The mixture wasfiltered and concentrated. The crude product was purified by radialchromatography using 15% ethyl acetate in hexanes to give a tan solid(0.25 g, 57%). ¹H NMR (400 MHz, CDCl₃) δ 6.66 (d, J=2.9 Hz, 1H), 6.62(d, J=8.8 Hz, 1H), 6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.56 (s, 1H), 4.40 (s,1H), 4.25 (q, J=7.2 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.63 (q, J=7.5 Hz,2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 239(M+1).

Step D{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-propylphenoxy)acetic acidethyl ester

A mixture of (4-hydroxy-2-propylphenoxy)acetic acid ethyl ester (0.23 g,0.965 mmol), toluene-4-sulfonic acid2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester (Japan Tobacco Inc WO9518125) (0.41 g, 1.16 mmol), and cesium carbonate (0.41 g, 1.25 mmol)was heated at 55° C. in DMF (45 mL) for 18 h. The reaction mixturecooled, concentrated in vacuo, and partitioned between EtOAc (60 mL) andH₂O (40 mL). The organic layer was washed with brine, dried (Na₂SO₄),and concentrated. The crude product was purified by radialchromatography using 15% ethyl acetate in hexanes to give a tan solid(0.25 g, 61%). ¹H NMR (400 MHz, CDCl₃) δ 7.97, (dd, J=8.3, 2.0 Hz, 2H),7.45-7.39 (m, 3H), 6.73 (s, 3H), 6.65 (d, J=1.5 Hz, 2H), 4.55 (s, 2H),4.24 (q, J=7.2 Hz, 2H), 4.18 (t, J=6.8 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H),2.37 (s, 3H), 1.62 (q, J=7.5 Hz, 2H), 1.52 (s, 6H), 1.27 (t, J=7.1 Hz,3H), 1.08 (t, J=7.3 Hz, 3H); MS (FIA) m/e 424 (M+1).

The following compound was prepared by the same procedure using ethylbromoisobutyrate in step B:

2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-propylphenoxy}propionicacid ethyl ester: ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=8.3, 2.4 Hz,2H), 7.43-7.41 (m, 3H), 6.70 (d, J=2.9 Hz, 1H), 6.63-6.58 (m, 2H), 4.23(q, J=−7.2 Hz, 2H), 4.18 (t, J=6.6 Hz, 2H), 2.95 (t, J=6.6 Hz, 2H), 2.54(t, J=7.6 Hz, 2H), 2.36 (s, 3H), 1.59 (q, J=7.5 Hz, 2H), 1.53 (s, 6H),1.26 (t, J=7.1 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H); MS (FIA) m/e 452 (M+1).

Step E{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-2-propylphenoxy}acetic acid

A solution of2-methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-propylphenoxy}propionicacid ethyl ester (0.21 g, 0.5 mmol) in MeOH (10 mL) was treated with2.5N aqueous NaOH (1.2 mL). The solution was heated at 55° C. for 1.5 h,cooled to ambient temperature, and concentrated in vacuo. The residuewas diluted with EtOAc (30 mL) and water (30 mL) and acidified to pH=1with 5N aqueous HCl. The organic layer was washed with brine (40 mL),dried (Na₂SO₄), and concentrated to a white solid (0.17 g, 86%). ¹H. NMR(400 MHz, CDCl₃) δ 7.97 (dd, J=7.4, 2.4 Hz, 2H), 7.44-7.41 (m, 3H), 6.72(d, J=2.9 Hz, 1H), 6.68-6.59 (m, 2H), 4.59 (s, 2H), 4.14 (t, J=6.6 Hz,2H), 2.97 (t, J=6.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.61(q, J=7.7 Hz, 2H), 0.94 (t, J=7.6 Hz, 3H); MS (ES) m/e 396 (M+1).

The following compound was also prepared from the corresponding ester:

Example 26A2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-propylphenoxy}propionicacid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=8.3, 2.9 Hz, 2H), 7.44-7.40 (m,3H), 6.77 (d, J=8.8 Hz, 1H), 6.71 (d, J=2.9 Hz, 1H), 6.59 (dd, J=8.8,2.9 Hz, 1H), 4.15 (q, J=6.6 Hz, 2H), 2.98 (t, J=6.6 Hz, 2H), 2.52 (t,J=7.6 Hz, 2H), 2.37 (s 3H), 1.59 (q, J=7.5 Hz, 2H), 1.54 (s, 6H), 0.93(t, J=7.3 Hz, 3H); MS (ES) m/e 424 (M+1).

Example 27{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-3-propylphenoxy)acetic acid

Step A 4-[2-(4-Benzyloxy-2-propylphenoxy)ethyl]-5-methyl-2-phenyloxazole

A solution of 4-benzyloxy-2-propylphenol (1.00 g, 4.13 mmol),2-(5-methyl-2-phenyloxazol-4-yl)ethanol (Japan Tobacco Inc WO 9518125)(0.84 g, 4.13 mmol), and triphenylphosphine (1.41 g, 5.37 mmol) in THF(17 mL) was treated dropwise at ambient temperature with diisopropylazodicarboxylate (0.96 mL, 5.0 mmol). After 18 h, the reaction mixturewas concentrated in vacuo. The residue was diluted with EtOAc, washedwith brine (40 mL), dried (Na₂SO₄), and concentrated. The crude productwas purified by radial chromatography using 10-15% ethyl acetate inhexanes to give the product (1.2 g, 68%). ¹H. NMR (400 MHz, CDCl₃) δ7.98 (dd, J=7.8, 2.4 Hz, 2H), 7.45-7.30 (m, 8H), 6.78-6.69 (m, 3H), 4.99(s, 2H), 4.19 (t, J=6.6 Hz, 2H), 2.96 (t, J=6.4 Hz, 2H), 2.50 (t, J=7.6Hz, 2H), 2.38 (s, 3H), 1.53 (q, J=7 Hz, 2H), 0.88 (t, J=7 Hz, 3H); MS(FIA) m/e 428 (M+1).

Step B 4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-3-propylphenol

A solution of4-[2-(4-benzyloxy-2-propylphenoxy)ethyl]-5-methyl-2-phenyloxazole. (1.2g, 2.8 mmol) in THF (50 mL) was treated with 5% Pd/C (0.15 g) andhydrogen (60 psi) at ambient temperature for 18 h. The mixture wasfiltered and concentrated. The crude product was purified by radialchromatography using 15% ethyl acetate in hexanes to give a tan solid(0.74 g, 78%): ¹H. NMR (400 MHz, CDCl₃) δ 7.99 (dd, J=7.8 Hz, 2.4 Hz,2H), 7.44-7.39 (m, 3H), 6.65-6.47 (m, 3H), 4.11 (t, J=6.4 Hz, 2H), 2.95(t, J=6.4 Hz, 2H), 2.43 (t, J=7.8 Hz, 2H), 2.39 (s, 3H), 1.46 (q, J=7.2Hz, 2H), 0.85 (t, J=7 Hz, 3H).

Step C{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)ethoxy]-3-propylphenoxy}acetic acidethyl ester

A solution of 4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-3-propylphenol(0.37 g, 1.10 mmol) in dry DMF (4 mL) was cooled in an ice bath andtreated with NaH (0.13 g, 3.3 mmol, 60% oil dispersion). After 10 min,ethyl bromoacetate (0.37 mL, 3.3 mmol) was added. The ice bath wasremoved, and the mixture was placed in an oil bath (T=85° C.). After 18h, the reaction mixture was cooled and concentrated in vacuo. Theresidue was partitioned between EtOAc (70 mL) and water (40 mL). Theorganic layer was dried (Na₂SO₄) and concentrated. The crude product waspurified by radial chromatography using 5% ethyl acetate indichloromethane to give a white solid (0.34 g, 73%). ¹H NMR (400 MHz,CDCl₃), δ 7.97 (dd, J=7.8, 2.4 Hz, 2H), 7.41-7.39 (m, 3H), 6.77-6.73 (m,2H), 6.61-6.63 (m, 1H, 4.54 (s, 1H), 4.28-4.24 (m, 2H), 2.96 (t, J=6.4Hz, 2H), 2.50 (t, J=7.1 Hz, 2H), 2.37 (s, 3H), 1.51 (q, J=7.6 Hz, 2H),1.31-1.29 (m, 5H), 0.84 (t, J=7.0 Hz, 3H); MS (FIA) m/e 424 (M+1).

Step D{4-[9-(5-Methyl-2-phenyloxazol-4-yl)-ethoxy]-3-propylphenoxy}acetic acid

A solution of{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-3-propylphenoxy}acetic acidethyl ester (0.10 g, 0.24 mmol) in MeOH (5 mL) was treated with 2.5 Naqueous NaOH (0.52 mL). The solution was heated at 55° C. for 2 h,cooled to ambient temperature, and concentrated in vacuo. The residuewas diluted with EtOAc (40 mL) and water (40 mL) and acidified to pH=1with 5N aqueous HCl. The organic layer was washed with brine (40 mL),dried (Na₂SO₄), and concentrated to give a white solid (0.080 g, 86%).¹H NMR (400 MHz, CDCl₃), δ 7.97 (dd, J=7.8, 2.9 Hz, 2H), 7.44-7.40 (m,3H), 6.76 (d, J=2.9 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.64 (dd, J=8.8,2.9 Hz, 1H), 4.58 (s, 2H), 4.14 (t, J=6.4 Hz, 2H), 2.99 (t, J=6.4 Hz,2H), 2.39 (s, 3H), 1.51 (q, J=7.5 Hz, 2H), 0.88 (t, J=7.3 Hz, 3H); MS(FIA) m/e 396 (M+1).

The following compound was also prepared by the same procedure usingethyl bromoisobutyrate in step C:

Example 27A2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-3-propylphenoxy}propionicacid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=8.3, 2.4 Hz, 2H), 7.43-7.40 (m,3H), 6.75-6.72 (m, 3H), 4.18 (t, J+6.4 Hz, 2H), 3.00 (t, J=6.4 Hz, 2H),2.49 (t, J=7.6 Hz, 2H), 2.39 (s, 3H), 1.53-1.48 (m, 8H), 0.87 (t, J=7.3Hz, 3H); Rf=0.59 (20% MeOH/CH₂Cl₂).

Example 28{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2,6-dipropyl-phenoxy}aceticacid

Step A 2-Allyl-1-allyloxy-4-benzyloxy-benzene

A mixture of 2-allyl-4-benzyloxy-phenol (ER2-YYR-17) (35.56 g, 148mmol), allyl bromide (21.5 g, 178 mmol), cesium carbonate (58 g, 178mmol) and methyl ethyl ketone (400 mL) was refluxed with stirring in a 1L round bottomed flask. After 23 h, the reaction was cooled andconcentrated. The residue was partitioned between water (500 mL) andEtOAc (400 mL). The organic layer was dried (MgSO₄) and concentrated toa tan oil, 39.37 (95%) ERO-LKW-190A: ¹H NMR (CDCl₃) δ 3.45 (dd, 2H),4.54 (dd, 2H), 5.04 (s, 2H), 5.18 (m, 2H), 5.29 (dd, 1H), 5.46 (dd, 1H),5.94-6.18 (m, 2H), 6.81 (s, 2H), 6.88 (s, 1H), 7.30-7.48 (m, 5H), MS(ES) m/e 281 [M+1]

Step B 2,6-Diallyl-4-benzyloxy-phenol

A mixture of 2-allyl-1-allyloxy-4-benzyloxy-benzene (5.45 g, 19.44 mmol)and N,N-dimethylaniline (DMA) (5 mL) was heated at reflux for 5 h. Thereaction was cooled and 1N H₂SO₄ (50 mL) was added. The product wasextracted into EtOAc (100 mL) and washed with 1N H₂SO₄ (2×100 mL). Theorganic layer was dried (MgSO₄) and concentrated to a dark brown oil5.45 g. The crude product was purified by flash chromatography (300 gsilica gel/6% EtOAc/hexane) to give a yellow oil 3.10 (57%): ¹H NMR(CDCl₃) δ 3.44 (dd, 4H), 4.83 (s, 1H), 5.04 (s, 2H), 5.19 (dd, 4H),5.97-6.14 (m, 2H), 6.72 (s, 2H), 7.33-7.52 (m, 5H), MS (ES) m/e 281[M+1].

Step C (2,6-Diallyl-4-benzyloxy-phenoxy)-acetic acid ethyl ester

2,6-Diallyl-4-benzyloxy-phenol (1.507 g, 5.37 mmol), ethyl bromoacetate(0.89 mL, 8.0 mmol), and cesium carbonate (1.75 g, 5.37 mmol) in dry DMF(15 mL) were heated at 85° C. for 18 h. The reaction mixture was cooledand partitioned between water (25 mL) and ethyl acetate (75 mL). Theorganic layer was washed with brine (25 mL), dried (Na₂SO₄), andconcentrated to an oil (2.08 g, 105%): ¹H NMR (400 MHz, CDCl₃) δ 1.32(t, 3H, J=7.3 Hz), 3.41 (d, 2H, J=6.3 Hz), 4.28 (q, 2H, J=7.3 Hz), 4.34(s, 2H), 4.98 (s, 2H), 5.02-5.09 (m, 4H), 5.94 (ddt, 2H, J=5.1, 10.3,16.6 Hz), 6.68 (s, 2H), 7.29-7.42 (m, 5H).

The following compound was prepared by the same procedure:2-(2,6-Diallyl-4-benzyloxy-phenoxy)-2-methyl-propionic acid ethyl ester:¹H NMR (400 MHz, CDCl₃) δ 1.30 (t, 3H, J=7.3 Hz), 1.41 (s, 6H), 3.29 (d,4H, J=6.8 Hz), 4.23 (q, 2H, J=7.1 Hz), 4.92 (s, 2H), 5.02-5.06 (m, 2H),5.06 (s, 2H), 5.80-5.90 (m, 2H), 6.61 (s, 2H), 7.27-7.38 (m, 5H).

Step D (4-Hydroxy-2,6-dipropyl-phenoxy)-acetic acid ethyl ester

(2,6-Diallyl-4-benzyloxy-phenoxy)-acetic acid ethyl ester (2.07 g, 5.65mmol) in ethanol (35 mL) was treated with 5% Pd/C (0.25 g) and hydrogen(60 psi, rt, 6 h). The mixture was filtered and concentrated to aviscous colorless oil (1.21 g, 76%): ¹H NMR (400 MHz, CDCl₃) δ 0.95 (t,6H, J=7.3 Hz), 1.28 (t, 4H, J=7.3 Hz), 1.61 (sextet, 4H, J=7.3 Hz),2.53-2.557 (m, 4H), 4.29 (q, 2H, J=7.2 Hz), 4.33 (s, 2H), 4.46 (brs,1H), 6.49 (s, 2H).

The following compound was prepared by the same procedure:2-(4-Hydroxy-2,6-dipropyl-phenoxy)-2-methyl-propionic acid ethyl ester:623 mg (80%).

Step E{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2,6-dipropyl-phenoxy}-aceticacid ethyl ester

A mixture of (4-hydroxy-2,6-dipropyl-phenoxy)-acetic acid ethyl ester(240 mg, 0.89 mmol), toluene-4-sulfonic acid2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (Japan Tobacco Inc WO9518125) (400 mg, 1.12 mmol), and Cs₂CO₃ (360 mg, 1.10 mmol) was heatedat 55 CC in DMF (5 mL) for 20 h. The reaction mixture cooled andpartitioned between EtOAc (30 mL) and H₂O (10 mL). The organic layer waswashed with brine (15 mL). The organic layer was dried (Na₂SO₄) andconcentrated. The crude product was purified by radial chromatographyusing hexanes:ethyl acetate (8:1 to 6:1) to give an oil (244 mg, 59%):¹H NMR (400 MHz, CDCl₃) δ 0.94 (t, 6H, J=7.3 Hz), 1.32 (t, 3H, J=7.0Hz), 1.60 (sextet, 4H, J=7.6 Hz), 2.39 (s, 3H), 2.53-2.56 (m, 4H), 3.05(brt, 2H), 4.20 (brt, 2H), 4.28 (q, 2H, J=7.3 Hz), 4.30 (s, 2H), 6.54(s, 2H), 7.45-7.50 (m, 3H), 8.02-8.09 (m, 2H).

The following compound was prepared by the same procedure:2-Methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2,6-dipropyl-phenoxy)-propionicacid ethyl ester: ¹H NMR (400 MHz, CDCl₃) δ 0.91 (t, 6H, J=7.3 Hz), 1.33(t, 3H, J=7.1 Hz), 1.41 (s, 6H), 1.59 (sextet, 4H, J=7.3 Hz), 2.33 (s,3H), 2.42-2.47 (m, 4H), 2.94 (t, 2H, J=66 Hz), 4.18 (t, 2H, J=6.8 Hz),4.26 (q, 2H, J=7.3 Hz), 6.52 (s, 2H), 7.38-7.43 (m, 3H), 7.96 (dd, 2H,J=1.5, 7.8 Hz).

Step F{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2,6-dipropyl-phenoxy}-aceticacid

A solution of{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2,6-dipropyl-phenoxy}-aceticacid ethyl ester (244 mg, 0.524 mmol) in THF (3 mL) and MeOH (6 mL) wastreated with 2.5N aqueous NaOH (2 mL). The solution was heated at 55° C.for 2.5 h, cooled to ambient temperature, and concentrated in vacuo. Theresidue was treated with ice water (1 mL) and acidified with 5N aqueousHCl (2 mL). The mixture with CH₂Cl₂ (3 mL) was transferred to aChemElute cartridge (5 g) and eluted with CH₂Cl₂ (40 mL). The eluent wasconcentrated to a white foam (228 mg, 100%): ¹H NMR (400 MHz, CDCl₃) δ0.94 (t, 6H, J=7.3 Hz), 1.60 (sextet, 4H, J=7.6 Hz), 2.37 (s, 3H),2.50-2.54 (m, 4H), 2.98 (brt, 2H), 4.19 (brt, 2H), 4.37 (s, 2H), 6.56(s, 2H), 7.42-7.43 (m, 3H), 7.98-7.99 (m, 2H); MS (ES) m/e 438.2 [M+1].

The following compound was hydrolyzed by the same procedure:

Example 28A2-Methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2,6-dipropyl-phenoxy}-propionicacid

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (t, 6H, J=7.3 Hz), 1.28 (s, 6H), 1.51(sextet, 4H, J=7.3 Hz), 2.34 (s, 3H), 2.41-2.46 (m, 4H), 2.88 (t, 2H,J=6.6 Hz), 4.51 (t, 2H, J=6.8 Hz), 6.54 (s, 2H), 7.46-7.54 (m, 3H),7.94-7.96 (m, 2H); MS (FIA) m/e 466.4 [M+1].

Example 292-Methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenoxy}-propionicacid

and2-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenoxy}-2-methyl-propionicacid

Step A4-[2-(2,6-Diallyl-4-benzyloxy-phenoxy)-ethyl]-5-methyl-2-phenyl-oxazole

A mixture of 2,6-diallyl-4-benzyloxy-phenol (520 mg, 1.85 mmol),toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester(Japan Tobacco Inc WO 9518125) (828 mg, 2.32 mmol), and Cs₂CO₃ (604 mg,1.85 mmol) was heated at 55° C. in DMF (5 mL) for 20 h. Additionaltoluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester(300 mg, 0.839 mmol) and Cs₂CO₃ (200 mg, 0.614 mmol) were added, and themixture was heated for 18 h. The reaction mixture was cooled andpartitioned between EtOAc (40 mL) and H₂O (10 mL). The organic layer waswashed with brine (15 mL), dried (Na₂SO₄), and concentrated. The crudeproduct was purified by radial chromatography using hexanes:ethylacetate (8:1) to give a colorless oil (722 mg, 83%): ¹H NMR (400 MHz,CDCl₃) δ 2.38 (s, 3H), 2.95 (t, 2H, J=6.3 Hz), 3.33 (d, 2H, J=6.3 Hz),4.01 (t, 2H, J=6.3 Hz), 4.96 (s, 2H), 4.97-5.02 (m, 2H), 5.03 (s, 2H),5.84-5.94 (m, 1H), 6.65 (s, 2H), 7.28-7.45 (m, 8H), 7.99 (dd, 2H, J=2.0,7.8 Hz).

Step B 4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenoland 4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenol

4-[2-(2,6-Diallyl-4-benzyloxy-phenoxy)-ethyl]-5-methyl-2-phenyl-oxazole(722 mg, 1.54 mmol) in ethanol (35 mL) was treated with 5% Pd/C (0.90 g)and hydrogen (60 psi, rt, 18 h). The mixture was filtered andconcentrated to a viscous colorless oil (377 mg, 76%) as a ˜1:1 molarmixture of the title compounds: ¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, 3H,J=7.3 Hz), 0.88 (t, 3H, J=7.3 Hz), 1.20-1.40 (m, 1.5H), 1.45-1.58 (m,6H), 1.65-1.75 (m, 1H), 1.78-1.82 (m, 1H), 1.98-2.05 (m, 1H), 2.26 (s,1.5H), 2.39 (s, 1.5), 2.37-2.45 (m, 4H), 2.82-2.88 (m, 1H), 2.94 (t, 1H,J=6.3 Hz), 3.84 (t, 1H, J=6.3 Hz), 3.93 (t, 1H, J=6.3 Hz), 6.44 (brs,2H), 7.38-7.42 (m, 1.5H), 7.98-8.00 (m, 1H).

Step C2-Methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenoxy)-propionicacid ethyl ester and2-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenoxy}-2-methyl-propionicacid ethyl ester

A mixture of4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenol and4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenol(377 mg, 0.993 mmol), ethyl bromoisobutyrate (0.29 mL, 2.0 mmol), andCs₂CO₃ (326 mg, 1.00 mmol) was heated at 55° C. in DMF (5 mL) for 16 h.Additional bromo ester (0.29 mL) and Cs₂CO₃ (326 mg) were added, and themixture was heated for 7 h. The reaction mixture cooled and partitionedbetween EtOAc (30 mL) and H₂O (10 mL). The organic layer was washed withbrine (10 mL), dried (Na₂SO₄), and concentrated. The crude product waspurified by flash chromatography using hexanes:ethyl acetate (100:0 to5:1) to give a colorless oil (450 mg, 92%), a −1:1 molar ratio of thetitle compounds: ¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, 3H, J=7.3 Hz), 0.88(t, 3H, J=7.3 Hz), 1.24 (2t, 3H, J=7 Hz), 1.2-1.4 (m, 1.5H), 1.45-1.58(m, 6H), 1.52 (s, 6H), 1.65-1.75 (m, 1H), 1.78-1.82 (m, 1H), 1.98-2.05(m, 1H), 2.25 (s, 1.5H), 2.38 (s, 1.5), 2.37-2.45 (m, 4H), 2.82-2.88 (m,1H), 2.94 (t, 1H, J=6 Hz), 3.85 (t, 1H, J=6 Hz), 3.95 (t, 1H, J=6 Hz),4.18 (2q, 2H, J=7 Hz), 6.44 (s, 2H), 7.38-7.42 (m, 1.5H), 7.98-8.00 (m,1H).

Step D2-Methyl-2-{4-[1-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenoxy}-propionicacid and2-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenoxy}-2-methyl-propionicacid

A solution of2-methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenoxy}-propionicacid ethyl ester and2-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenoxy}-2-methyl-propionicacid ethyl ester (450 mg, 0.966 mmol) in THF (5 mL) and MeOH (12 mL) wastreated with 2 N aqueous NaOH (3 mL). The solution was heated at 55° C.for 2 h, cooled to ambient temperature, and concentrated in vacuo. Theresidue was acidified with 5N aqueous HCl (1 mL) and partitioned betweenEtOAc (30 mL) and H₂O (5 mL). The organic layer was washed with brine(10 mL), dried (Na₂SO₄), and concentrated to a colorless oil (450 mg).The mixture was separated using HPLC to give the title compounds aswhite foams.

Example 29A2-Methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenoxy}-propionicacid:

¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, 6H, J=7.3 Hz), 1.51 (s, 6H), 1.51(sextet, 4H, J=7.8 Hz), 2.39 (s, 3H), 2.42-2.46 (m, 4H), 2.96 (t, 2H,J=6.4 Hz), 3.96 (t, 2H, J=6.4 Hz), 6.57 (s, 2H), 7.41-7.43 (m, 3H),7.98-8.01 (m, 2H).

Example 29B2-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-3,5-dipropyl-phenoxy}-2-methyl-propionicacid:

(482878) ¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, 6H, J=7.3 Hz), 1.20-1.40 (m,3H), 1.24-1.60 (m, 6H), 1.52 (s, 6H), 1.68-1.71 (m, 1H), 1.78-1.83 (m,2H), 2.00-2.03 (m, 2H), 2.26 (s, 3H), 2.40 (t, 4H, J=7.8 Hz), 2.70-2.80(m, 1H), 2.86 (t, 2H, J=6.1 Hz), 3.86 (t, 2H, J=6 Hz), 6.56 (s, 2H).

Example 30{2-Ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}acetic acid

Step A 4-Benzyloxy-2-vinylphenol

To a flame dried 500 mL 3-neck flask under an atmosphere of argon, wascharged methyltriphenylphosphonium bromide (43.8 mmol) dissolved inanhydrous THF (120 mL) followed by the dropwise addition ofn-butyllithium (21.9 mL, 35.04 mmol). The dark red mixture was stirredat ambient temperature for 1 h. Next 5-benzyloxy-2-hydroxybenzaldehyde(2.0 g, 8.76 mmol) (Acta. Chem. Scand., Ser. B, B40(5), 400-1, (1986)was added followed by the addition of anhydrous dichloromethane (40 mL).The mixture was stirred at ambient temperature for 18 h. The solventswere removed in vacuo, and the residue was partitioned between EtOAc andwater (500 mL each). The organic layer was washed with brine (500 mL),dried (Na₂SO₄), and concentrated in vacuo. The crude product waspurified using the Biotage FlashElute chromatography system using a 65Mnormal phase cartridge, eluting with 15% EtOAc/Hexanes to give a yellowsolid (1.75 g, 88%). ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.30, (m, 4H), 7.14(d, J=2.9 Hz, 1H), 6.94-6.87 (m, 1H), 6.79 (dd, J=8.8, 2.9 Hz, 2H), 6.72(d, J=8.8 Hz, 1H), 5.71 (dd, J=17.6, 1.5 Hz, 1H), 5.35 (dd, J=11.2, 0.98Hz, 1H), 5.02 (s, 2H), 4.60 (s, 1H); MS (FIA) m/e 227 (M+1).

Step B (4-Benzyloxy-2-vinylphenoxy)acetic acid ethyl ester

4-Benzyloxy-2-vinylphenol (0.40 g, 1.77 mmol) was dissolved in anhydrousDMF (4 mL), followed by the addition of ethyl bromoacetate (0.29 mL,2.65 mmol), and cesium carbonate (0.75 g, 2.30 mmol). The mixture wasthen heated for 18 h (55° C.). The reaction mixture was then cooled andconcentrated in vacuo. The crude residue was partitioned between EtOAc(70 mL) and water (40 mL). The organic layer was washed with brine,dried (Na₂SO₄), and removed in vacuo to give 0.56 g (100%) of a yellowsolid: ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.31 (m, 4H), 7.13 (d, J=2.9 Hz,1H), 7.10-7.06 (m, 1H), 6.82 (dd, J=8.8, 2.9 Hz, 1H), 6.73 (d, J=9.3 Hz,1H), 5.76 (dd, J=17.1 Hz, 1.5 Hz, 1H), 5.30 (dd, J=11.2, 1.5 Hz, 1H),5.03 (s, 2H), 4.58 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.1 Hz,3H); MS (FIA) m/e 313 (M+1).

Step C (2-Ethyl-4-hydroxyphenoxy)acetic acid ethyl ester

A solution of (4-benzyloxy-2-vinylphenoxy)acetic acid ethyl ester (0.55g, 1.77 mmol) in ethanol (15 mL) was treated with 5% Pd/C (70 mg) andhydrogen (60 psi) at ambient temperature for 18 h. The mixture wasfiltered and concentrated in vacuo to give a tan oil (0.31 g, 77%): ¹HNMR (400 MHz, CDCl₃) δ 6.68 (d, J=2.9 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H),6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.62 (s, 1H), 4.57 (s, 2H), 4.25 (q, J=7.2Hz, 2H), 3.73 (q, J=7.0 Hz, 2H), 2.66 (q, J=7.7 Hz, 2H), 1.34-0.92 (m,6H); MS (FIA) m/e 225 (M+1).

Step D {2-Ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}aceticacid ethyl ester

A mixture of (2-ethyl-4-hydroxyphenoxy)acetic acid ethyl ester (0.29 g,1.29 mmol), toluene-4-sulfonic acid2-(5-methyl-2-phenyloxazol-4-1yl)ethyl ester (0.55 g, 1.55 mmol), andcesium carbonate (0.55 g, 1.7 mmol) in anhydrous DMF (4 mL) was heatedfor 18 h (55° C.). The mixture was concentrated in vacuo, and theresidue was partitioned between EtOAc (100 mL) and water (50 mL), washedwith brine (50 mL), dried (Na₂SO₄), and removed in vacuo to give a crudeoil which was purified using radial chromatography eluting with 10-15%EtOAc/Hexanes to give 0.24 g (38%) of a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.97 (dd, J=7.8, 2.4 Hz, 2H), 7.44-7.39 (m, 3H), 6.75 (s, 1H),6.65 (d, J=1.5 Hz, 2H), 4.56 (s, 2H), 4.24 (q, J=7.2 Hz, 2H), 4.19 (t,J=6.6 Hz, 2H), 2.95 (t, J=6.8 Hz, 2H), 2.67 (q, J=7.5 Hz, 2H), 2.37 (s,3H), 1.28 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.6 Hz, 3H); MS (FIA) m/e 424(M+1).

The following compounds were also prepared by this procedure:

2-{2-Ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-phenoxy}2-methylpropionicacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.8, 2.4 Hz,2H), 7.44-7.39 (m, 3H), 6.72 (d, J=2.9 Hz, 1H), 6.64-6.52 (m, 2H), 4.24(q, J=7.0 Hz, 2H), 4.18 (t, J=6.8 Hz, 2H), 2.95 (t, J=6.8 Hz, 2H), 2.60(q, J=7.5 Hz, 2H), 2.36 (s, 3H), 1.53 (s, 6H), 1.26 (t, J=7.6 Hz, 3H),1.17 (t, J=7.6 Hz, 3H); MS (FIA) m/e 438 (M+1).

{2-Isobutyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)aceticacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.98 (dd, J=7.8, 2.0 Hz,2H), 7.45-7.39 (m, 3H), 6.69-6.62 (m, 3H), 4.54 (s, 2H), 4.20 (q, J=7.5Hz, 2H), 4.11 (t, J=7.1 Hz), 2.96 (t, J=6.6 Hz, 2H), 2.50 (t, 6.1 Hz,2H), 2.37 (s, 3H), 1.87-2.00 (m, 1H), 1.24 (t, J=7.5 Hz, 3H), 0.87 (d,J=7 Hz, 6H); MS (ES) m/e 438 (M+1).

2-{2-Isobutyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.8, 2.0 Hz,2H), 7.45-7.39 (m, 3H), 6.66 (d, J=2.4 Hz, 1H), 6.18-6.53 (m, 2H), 4.22(q, J=7.00 Hz, 2H), 4.17 (t, J=6.8 Hz, 2H), 2.95 (t, J=6.6 Hz, 2H), 2.43(d, J=7.3 Hz, 2H), 2.36 (s, 3H), 1.96-1.89 (m, 1H), 1.53 (s, 6H), 1.26(t, J=5.9 Hz, 3H), 0.89 (d, J=7 Hz, 6H); MS (ES) m/e 466 (M+1).

[4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(5-phenylpentyl)phenoxy]aceticacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.98 (dd, J=8.3, 2.9 Hz,2H), 7.45-7.38 (m, 3H), 7.31-7.21 (m, 2H), 7.17-7.14 (m, 3H), 6.72 (d,J=1.5 Hz, 1H), 6.64 (d, J=1.5 Hz, 2H), 4-55 (s, 2H), 4.21 (q, J=7.2 Hz,2H), 4.13 (t, J=7.1 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 2.64-2.58 (m, 4H),2.37 (s, 3H), 1.67-1.49 (m, 4H), 1.25-1.35 (m, 2H), 1.28 (t, J=7.2 Hz,3H); MS (ES) m/e 528 (M+1).

2-Methyl-2-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(5-phenylpentyl)phenoxy]propionicacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.8, 2.4 Hz,2H), 7.44-7.39 (m, 3H), 7.28-7.25 (m, 3H), 7.18-7.14 (m, 3H), 6.69 (d,J=2.9 Hz, 1H), 6.63-6.56 (m, 2H), 4.22 (q, J=7.0 Hz, 2H), 4.17 (t, J=6.6Hz, 2H), 2.95 (t, J=6.6 Hz, 2H), 2.62-2.53 (m, 4H), 2.36 (s, 3H),1.68-1.47 (m, 4H), 1.51 (s, 6H), 1.27-1.42 (m, 2H), 1.12 (t, J=7.0 Hz,3H); MS (ES) m/e 556 (M+1).

{2-Butyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}acetic acidethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.98 (dd, J=7.8, 2.4 Hz, 2H),7.45-7.38 (m, 3H), 6.73 (s, 1H), 6.67-6.58 (m, 2H), 4.56 (s, 2H), 4.25(q, J=7.0 Hz, 2H), 4.18 (t, J=6.6 Hz, 2H), 2.95 (t, J=6.8 Hz, 2H), 2.63(t, J=7.6 Hz, 2H), 2.37 (s, 3H), 1.61-1.54 (m, 2H), 1.35 (q, J=7 Hz,2H), 1.28 (t, J=7 Hz, 3H), 0.95 (t, J=7.0 Hz, 3H); MS (ES) m/e 438(M+1).

2-{2-Butyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, 8.3, 2.0 Hz, 2H),7.45-7.39 (m, 3H), 6.70 (d, J=2.9 Hz, 1H), 6.61 (t, J=9.5 Hz, 1H), 6.57(dd, J=8.8, 2.9 Hz, 1H), 4.23 (q, J=7.2 Hz, 2H), 4.17 (t, J=6.8 Hz, 2H),2.95 (t, J=6.8 Hz, 2H), 2.56 (t, J=7.8 Hz, 2H), 2.36 (s 3H), 1.58-1.48(m, 8H), 1.28 (t, J=7 Hz, 3H), 0.90 (t, J=7.2 Hz, 3H); MS (ES) m/e 466(M+1).

2-{2-Cyclohexylmethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionicacid ethyl ester, MS (ES) m/e 506.3 (M+1).

2-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionicacid ethyl ester, MS (ES) m/e 582.3 (M+1).

2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionicacid ethyl ester, MS (ES) m/e 582.3 (M+1).

2-{2-Cyclohexylmethyl-4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenoxy)-2-methyl-propionicacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, 1H, J=3.9 Hz), 7.36(d, 1H, J=4.9 Hz), 7.08 (dd, 1H, J=3.7 Hz, J=4.9 Hz), 6.57-6.64 (m, 3H),4.23 (q, 2H, J=7.0), 4.15 (t, 2H, J=6.8 Hz), 2.92 (t, 2H, J=6.6 Hz),2.43 (d, 2H, J=6.8), 2.34 (s, 3H), 1.56-1.67 (m, 6H), 1.53 (s, 6H), 1.25(t, 3H, J=7.0 Hz), 1.12-1.19 (m, 3H), 0.89-0.98 (m, 2H), MS (ES) m/e512.3 (M+1).

2-{2-Cyclohexylmethyl-4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenoxy)-2-methyl-propionicacid ethyl ester, MS (ES) m/e 512.4 (M+1).

2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}propionicacid ethyl ester, MS (ES) m/e 515 (M+1).

2-{4-[2-(2-Cyclohexyl-5-methyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionicacid ethyl ester, MS (ES) m/e 520 (M+1).

2-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionicacid ethyl ester, MS (ES) m/e 590 (M+1).

2-{4-[2-(2-Biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionicacid ethyl ester, MS (ES) m/e 590 (M+1).

Step E {2-Ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}aceticacid

A solution of{2-ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)acetic acidethyl ester (0.22 g, 0.54 mmol) in ethanol (10 mL) was treated with 2.5N aqueous NaOH (0.4 mL), and heated at 55° C. for 2 h. The reaction wascooled to ambient temperature and concentrated down to near dryness. Theresidue was then diluted with EtOAc (40 mL) and water (20 mL) andacidified to pH=1 with 1N aqueous HCl. The organic layer was washed withbrine (20 mL), dried (Na₂SO₄) and concentrated in vacuo to give a whitesolid (0.18 g, 87%). ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=8.3, 2.9 Hz,2H), 7.44-7.41 (m, 3H), 6.75 (d, J=2.9 Hz, 1H), 6.69-6.60 (m, 2H), 4.60(s, 2H), 4.14 (t, J=6.6 Hz, 2H), 2.98 (t, J=6.60 Hz, 2H), 2.65 (q, J=7.5Hz, 2H), 2.38 (s, 3H), 1.19 (t, J=7.6 Hz, 3H); MS (FIA) m/e 382 (M+1).

The following compounds were also prepared from their correspondingesters:

Example 30A2-{2-Ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}2-methylpropionicacid

¹H NMR (400 MHz, CDCl₃) 8 (dd, J=7.8, 2.4 Hz, 2H), 7.45-7.40 (m, 3H),6.79-6.58 (m, 3H), 4.16 (t, J=6.6 Hz, 2H), 2.98 (t, J=6.4 Hz, 2H), 2.59(q, J=7.5 Hz, 2H), 2.38 (s, 3H), 1.55 (s, 6H), 1.18 (t, J=7.6 Hz, 3H);MS (FIA) m/e 410 (M+1).

Example 30B{2-Isobutyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}aceticacid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.8, 2.9 Hz, 2H), 7.46-7.39 (m,3H), 6.69-6.61 (m, 3H), 4.58 (s, 2H), 4.14 (t, J=6.6 Hz, 2H), 2.97 (t,J=6.8 Hz, 2H), 2.48 (d, J=7.3 Hz, 2H), 2.38 (s, 3H), 1.95-1.86 (m, 1H),0.90 (d, J=6.8 Hz, 6H); MS (ES) m/e 410 (M+1).

Example 30C2-{2-Isobutyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.3, 2.4 Hz, 2H), 7.44-7.40 (m,3H), 6.76 (d, J=8.8 Hz, 1H), 6.67 (d, J=3.4 Hz, 1H), 6.59 (dd, J=8.8,2.9 Hz, 1H), 4.15 (t, J=6.6 Hz, 2H), 2.98 (t, J=6.6 Hz, 2H), 2.42 (d,J=6.8 Hz, 2H), 2.37 (s, 3H), 1.93-1.86 (m, 1H), 1.55 (s, 6H), 0.89 (d,J=6.4 Hz, 6H); MS (FIA) m/e 424 (M+1).

Example 30D[4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(5-phenylpentyl)phenoxy]aceticacid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.8, 2.9 Hz, 2H), 7.44-7.40 (m,3H), 7.27-7.21 (m, 2H), 7.17-7.14 (m, 3H), 6.71 (d, J=2.4 Hz, 1H), 6.66(d, J=8.8 Hz, 1H), 6.60 (dd, J 2.9, 2.9 Hz, 1H), 4.57 (s, 2H), 4.13 (t,J=6.8 Hz, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.62-2.56 (m, 4H), 2.37 (s, 3H),1.67-1.57 (m, 4H), 1.42-1.33 (m, 2H); MS (ES) m/e 500 (M+1).

Example 30E2-Methyl-2-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(5-phenylpentyl)phenoxy]propionicacid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=8.3, 2.9 Hz, 2H), 7.45-7.38 (m,3H), 7.31-7.28 (m, 2H), 7.25-7.15 (m, 3H), 6.77 (d, J=8.8 Hz, 1H), 6.66(d, J=2.9 Hz, 1H), 6.59 (dd, J 8.8, 3.4 Hz, 1H), 4.16 (t, J=6.6 Hz, 2H),2.98 (t, J=6.6 Hz, 2H), 2.61-2.52 (m, 4H), 2.37 (s, 3H), 1.70-1.50 (m,8H), 1.23-1.33 (m, 2H); MS (ES) m/e 528 (M+1).

Example 30F{2-Butyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}acetic acid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.8, 2.9 Hz, 2H), 7.45-7.39 (m,3H), 6.72 (d, J=2.4 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 6.60 (d, J=8.3 Hz,1H), 4.56 (s, 2H), 4.13 (t, J=6.6 Hz, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.60(t, J=7.6 Hz, 2H), 2.37 (s, 3H), 1.55 (quintet, J=7.5 Hz, 2H), 1.36(quintet, J=7.5 Hz, 2H), 0.89 (t, J=7.3 Hz, 3H); MS (ES) m/e 410 (M+1).

Example 30G2-{2-Butyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]phenoxy}-2-methylpropionicacid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.8, 2.4 Hz, 2H), 7.45-7.40 (m,3H), 6.77 (d, J=9.3 Hz, 1H), 6.71 (d, J=3.4 Hz, 1H), 6.59 (dd, J=8.8,2.9 Hz, 1H), 4.16 (t, J=6.6 Hz, 2H), 4.16 (t, J=6.6 Hz, 2H), 2.98 (t,J=6.6 Hz, 2H), 2.55 (t, J=7.8 Hz, 2H), 2.38 (s, 3H), 1.58-1.50 (m, 8H),1.34 (quintet, J=7.5 Hz, 2H), 0.92 (t, J=7.3 Hz, 3H); MS (ES) m/e 438(M+1).

Example 30H2-{2-Cyclohexylmethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionicacid

¹H NMR (400 MHz, CDCl₃) δ 7.94-7.96 (m, 2H), 7.41-7.45 (m, 3H), 6.73 (d,1H, J=8.8 Hz), 6.61 (d, 1H, J=3.4 Hz), 6.57 (dd, 1H, J=8.8 Hz, J=2.9Hz), 4.13 (t, 2H, J=6.4 Hz), 3.00 (t, 2H, J=6.1 Hz), 2.37 (s, 3H),1.59-1.61 (m, 4H), 1.49 (s, 6H), 1.21 (s, 2H), 1.10-1.14 (m, 5H),0.84-0.90 (m, 2H), MS (ES) m/e 478.2 (M+1).

Example 30I2-{2-Cyclohexylmethyl-4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionicacid

¹H NMR (400 MHz, CDCl₃) δ 6.74 (d, 1H, J=8.8 Hz), 6.61 (d, 1H, J=2.9Hz), 6.57 (dd, 1H, J=8.8 Hz, J=2.9 Hz), 4.11 (t, 2H, J=5.9 Hz), 2.99 (t,2H, J=5.6 Hz), 2.39 (d, 2H, J=7.3 Hz), 2.33 (s, 3H), 2.01-2.04 (m, 1H),1.80-1.83 (m, 1H), 1.58-1.64 (m, 5H), 1.51 (s, 6H), 0.85-1.41 (m, 15H),MS (ES) m/e 484.3 (M+1).

Example 30J:2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}propionicacid)

¹H NMR (400 MHz, CDCl₃) δ 7.99 (dd, J=6.8, 2.9 Hz, 2H), 7.47-7.46 (m,3H), 7.31-7.14 (m, 5H), 6.75-6.71 (m, 2H), 6.62 (dd, J=8.8, 2.9 Hz, 1H),4.16 (t, J=6.1 Hz, 2H), 3.02 (t, J=6.1 Hz, 2H), 2.85 (s, 4H), 2.41 (s,3H), 1.53 (s, 6H), MS (ES) m/e 486 (M+1).

Example 30K2-{4-[2-(2-Cyclohexyl-5-methyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionicacid)

¹H NMR (400 MHz, CDCl₃) δ 7.31-7.15 (m, 5H), 6.74-6.68 (m, 3H), 6.58(dd, J 8.8, 2.9 Hz, 1H), 4.08 (t, J=6.1 Hz, 2H), 2.95 (t, J=6.1 Hz, 2H),2.86 (s, 4H), 2.31 (s, 3H), 2.26-2.02 (m, 2H), 1.84-1.81 (m, 2H),1.74-1.71 (m, 1H), 1.61-1.58 (m, 7H), 1.49-1.25 (m, 4H), MS (ES) m/e 492(M+1).

Example 31{3-Ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}acetic acid

Step A 4-[2-(4-Benzyloxy-2-vinylphenoxy)ethyl]-5-methyl-2-phenyloxazole

A mixture of 4-benzyloxy-2-vinylphenol (0.88 g. 3.89 mmol),toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester(1.67 g (4.67 mmol) and cesium carbonate (1.65 g (5.06 mmol) inanhydrous DMF (8 mL) was heated for 18 h at 55° C. The mixture wasconcentrated in vacuo, and the residue was partitioned between EtOAc(100 mL) and water (50 mL), washed with brine (50 mL), dried (Na₂SO₄),and removed in vacuo to give a crude oil which was purified using theBiotage FlashElute chromatography system using a 40L normal phasecartridge, eluting with 10-15% EtOAc/Hexanes to give a white solid (1.35g, 84%): ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=8.3, 2.4 Hz, 2H),7.45-7.30 (m, 8H), 7.11 (d, J=2.0 Hz, 1H), 7.10-6.95 (m, 1H), 6.82 (d,J=1.5 Hz, 2H), 5.68 (dd, J=18.1, 1.5 Hz, 1H), 5.22 (dd, J=11.2, 1.5 Hz,1H), 5.02 (s, 2H), 4.23 (t, J=6.6 Hz, 2H), 2.98 (t, J=6.6 Hz, 2H), 2.37(s, 3H); MS (FD) m/e 411 (M+).

Step B 3-Ethyl-4-[2-(5-methyl-2-phenyloxazole-4-yl)ethoxy]phenol

A solution of4-[2-(4-benzyloxy-2-vinylphenoxy)ethyl]-5-methyl-2-phenyloxazole (1.30g, 3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) andhydrogen (60 psi) at ambient temperature for 18 h. The mixture wasfiltered and concentrated in vacuo to give a tan solid (0.65 g, 64%): ¹HNMR (400 MHz, CDCl₃) δ 7.99 (dd, J=8.3 Hz, 2.0 Hz, 2H), 7.45-7.38 (m,3H), 6.63 (d, J=2.4 Hz, 1H), 6.50-6.41 (m, 2H), 5.98 (br s, 1H), 4.10(t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.85-2.51 (m, 2H), 2.39 (s,3H), 1.08 (t, J=7 Hz, 3H); HRMS: Calc'd=324.1599; Found=324.1597.

Step C{3-Ethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]phenoxy}acetic acidethyl ester

A mixture of 3-ethyl-4-[2-(5-methyl-2-phenyloxazole-4-yl)ethoxy]phenol(0.29 g. 0.90 mmol), ethyl bromoacetate (0.25 mL, 2.25 mmol) and cesiumcarbonate (0.45 g, (1.38 mmol) in anhydrous DMF (4 mL) was heated for 24h at 55° C. The mixture was concentrated in vacuo, and the residue waspartitioned between EtOAc (50 mL) and water (40 mL), washed with brine,dried (Na₂SO₄), and removed in vacuo to give a crude oil which waspurified using radial chromatography eluting with 2% EtOAc/MeCl₂ to givea white solid (0.25 g, 68%): ¹H NMR (400 MHz, CDCl₃) δ 7.97 dd, J=8.3,2.4 Hz, 2H), 7.45-7.39 (m, 3H), 6.75 (dd, J=8.3, 2.0 Hz, 2H), 2H), 6.64(dd, J=8.8, 3.4 Hz, 1H), 4.55 (s, 2H), 4.24 (q, J=6.5 Hz, 2H), 4.10 (t,J=6.4 Hz, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.57 (t, J=7.3 Hz, 2H), 2.37 (s,3H), 1.29 (t, J=7.3 Hz, 3H), 1.12 (t, J=6.5 Hz, 3H); MS (ES) m/e 410(M+1)

The following compounds were also prepared by this procedure:

2-{3-Ethyl-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}2-methylpropionicacid ethyl ester: ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.3, 2.9 Hz,2H), 7.45-7.39 (m, 3H), 6.72-6.61 (m, 3H), 4.25-4.17 (m, 4H), 2.96 (t,J=6.4 Hz, 2H), 2.53 (q, J=7.5 Hz, 2H), 1.52 (s, 6H), 1.27 (t, J=7.1 Hz,3H), 1.08 (t, J=7.3 Hz); MS (FIA) m/e 438 (M+1).

{3-Isobutyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}aceticacid ethyl ester: ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=8.3 Hz, 2H),7.45-7.39 (m, 3H), 6.77 (d, J=8.8 Hz, 1H), 6.70-6.64 (m, 2H), 4.54 (s,2H), 4.26 (q, J=7.2 Hz, 2H), 4.19 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz,2H), 2.38 (s, 3H), 1.84-1.77 (m, 1H), 1.32-1.28 (m, 5H), 0.82 (d, J=7Hz, 6H); MS (ES) m/e 438 (M+1).

2-{3-Isobutyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.8, 2.0 Hz,2H), 7.45-7.40 (m, 3H), 6.72-6.65 (m, 3H), 4.23 (q, J=7.1, 2.0 Hz, 2H),2.95 (t, J=6.4 Hz, 2H), 2.37-2.35 (m, 5H), 1.82-1.75 (m, 1H), 1.51 (s,6H), 1.27 (t, 6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 6H); MS (ES) m/e 466(M+1).

[4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-3-(5-phenylpentyl)phenoxy]aceticacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.96 (dd, J=7.8, 2.4 Hz,2H), 7.43-7.38 (m, 3H), 7.28-7.21 (m, 2H), 7.19-7.12 (m, 3H), 6.76 (d,J=8.8 Hz, 1H), 6.50 (d, J=3.4 Hz, 1H), 6.66-6.63 (m, 1H), 4.54 (s, 2H),4.27 (q, J=7.2 Hz, 2H), 4.19 (t, J=6.6 Hz, 2H), 2.95 (t, J=7 Hz, 2H),2.58-2.48 (m, 4H), 2.33 (s, 3H), 1.63-1.45 (m, 4H), 1.35-1.03 (m, 5H);MS (ES) m/e 528 (M+1)

2-Methyl-2-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-3-(5-phenyl-pentyl)phenoxy]propionicacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.96 (dd, J=7.3, 2.4 Hz,2H), 7.42-7.38 (m, 3H), 7.28-7.24 (m, 2H), 7.17 (d, J=7.3 Hz, 1H), 7.13(d, J=7.3 Hz, 2H), 6.71-6.62 (m, 3H), 4.22 (q, J=7.1 Hz, 2H), 4.19 (t,J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.56-2.46 (m, 4H), 2.33 (s, 3H),1.61 (s, 6H), 1.38-1.23 (m, 5H); MS (FIA) m/e 556 (M+1).

{3-Butyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)acetic acidethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.8, 2.0 Hz, 2H),7.45-7.37 (m, 3H), 6.77-6.72 (m, 2H), 6.64 (dd, J=8.8, 34 Hz, 1H), 4.54(s, 2H), 4.26 (q, J=7.0 Hz, 2H), 4.21 (t, J=6.6 Hz, 2H), 2.96 (t, J=6.4Hz, 2H), 2.52 (t, J=7.6 Hz, 2H), 2.37 (s, 3H), 1.50-1.43 (m, 21H),1.35-1.23 (m, 5H), 0.85 (t, J=7.0 Hz, 3H); MS (ES) m/e 438 (M+1).

2-{3-Butyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=8.3, 2.4 Hz,2H), 7.44-7.39 (m, 3H), 6.69 (d, J=2.4 Hz, 2H), 6.63 (dd, J=8.8, 2.9 Hz,1H), 4.22 (q, J=72 Hz, 2H), 4.19 (t, J=6.4 Hz, 2H), 2.96 (t, J=6.4 Hz,2H), 2.49 (t, J=7.6 Hz, 2H), 1.32-1.25 (m, 5H), 0.85 (t, J=7.2 Hz, 3H);MS (ES) m/e 466 (M+1).

2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-3-phenethylphenoxy}propionicacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J=5.9 Hz, 2H), 7.41(d, J=5.9 Hz, 3H), 7.22 (d, J=7.3 Hz, 2H). 7.16 (d, J=7.8 Hz, 1H), 7.11(d, J=7.3 Hz, 2H), 6.73 (d, J=9.3 Hz, 1H), δ 67 (d, J=7.8 Hz, 2H),4.24-4.11 (m, 4H), 2.96 (t, J=6.4 Hz, 2H), 2.80 (s, 4H), 2.31 (s, 3H),1.47 (s, 6H), 1.27 (t, J=7.1 Hz, 3H), MS (ES) m/e 514 (M+1).

2-{3-Cyclohexylmethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)-2-methylpropionicacid ethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=5.4, 2.4 Hz,2H), 7.43-7.39 (m, 3H), 6.72-6.63 (m, 3H), 4.25-4.17 (m, 4H), 2.95 (t,J=6.4 Hz, 2H), 2.97-2.93 (m, 5H), 1.59-1.52 (m, 10H), 1.46-1.38 (m, 2H),1.27 (t, J=7.1 Hz, 3H), 1.10-1.03 (m, 3H), 0.90-0.73 (m, 2H), MS (ES)m/e 506 (M+1).

2-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)ethoxy]phenoxy}-2-methyl-propionicacid ethyl ester. MS (ES) m/e 416.3 (M+1).

Step D {3-Ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}aceticacid

A solution of{3-ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxyacetic acidethyl ester (0.23 g, 0.57 mmol) in ethanol (10 mL) was treated with 2.5N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction wascooled to ambient temperature and concentrated down to near dryness. Theresidue was then diluted with EtOAc (40 mL) and water (20 mL) andacidified to pH=1 with 1N aqueous HCl. The organic layer was washed withbrine (20 mL), dried (Na₂SO₄) and concentrated in vacuo to give a whitesolid (0.18 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (dd, J=7.8, 2.9 Hz,2H), 7.46-7.40 (m, 3H), 6.79 (d, J=2.9 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H),6.63 (dd, J=8.8, 2.9 Hz, 1H), 4.58 (s, 2H), 4.14 (t, J=6.4 Hz, 2H), 3.01(t, J=6.4 Hz, 2H), 2.56 (q, J=7.5 Hz, 2H), 2.39 (s, 3H), 1.11 (t, J=7.6Hz, 3H); MS (ES) m/e 382 (M+1).

The following compounds were also prepared from their correspondingesters:

Example 31A2-{3-Ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid

¹H NMR (400 MHz, CDCl₃) δ 7.98 (dd, J=7.8, 2.4 Hz, 2H), 7.44-7.41 (m,3H), 6.77-6.69 (m, 3H), 4.18 (t, J=6.4 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H),2.55 (q, J=7.4 Hz, 2H), 2.39 (s, 3H), 1.53 (s, 6H), 1.10 (t, J=7.6 Hz,3H); MS (ES) m/e 410 (M+1).

Example 31B{3-Isobutyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}aceticacid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.3, 2.4 Hz, 2H), 7.45-7.42 (m,3H), 6.74-6.63 (m, 3H), 4.57 (s, 2H), 4.15 (t, J=6.4 Hz, 2H), 3.00 (t,J=6.4 Hz, 2H), 2.45-2.38 (m, 5H), 1.83-1.75 (m, 1H), 0.82 (d, J=6.4 Hz,6H); MS (ES) m/e 410 (M+1).

Example 31C2-{3-Isobutyl-4-[2-(5-methyl-2-phenyoxazol-4-yl)ethoxy]phenoxy)-2-methylpropionicacid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.8, 2.8 Hz, 2H), 7.45-7.40 (m,3H), 6.78-6.70 (m, 3H), 4.19 (t, J=6.4 Hz, 2H), 2.99 (t, J=6.4 Hz, 2H),2.39-2.34 (m, 5H), 1.83-1.76 (m, 1H), 1.51 (s, 6H), 0.81 (d, J=6.8 Hz,6H); MS (ES) m/e 438 (M+1).

Example 31D[4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-3-(5-phenylpentyl)phenoxy]aceticacid

¹H NMR (400 MHz, CDCl₃) 8.96 (dd, J=7.8, 2.0 Hz, 2H), 7.43-7.39 (m, 3H),7.28-7.24 (m, 2H), 7.18-7.12 (m, 3H), 6.74 (d, J=3.4 Hz, 1H), 6.71 (s,1H), 6.64 (dd, J=8.8, 2-9 Hz, 1H), 4.56 (s, 2H), 4.15 (t, J=6.4 Hz, 2H),2.98 (t, J=6.4 Hz, 2H), 2.56-2.51 (m, 4H), 2.49 (s, 3H), 1.61-1.48 (m,4H), 1.38-1.25 (m, 2H); MS (ES) m/e 500 (M+1).

Example 31E2-Methyl-2-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-3-(5-phenylpentyl)phenoxy]propionicacid

¹H NMR (400 MHz, CDCl₃) δ 0.96 (dd, J=7.3, 2.4 Hz, 2H), 7.41 (dd, J=8.8,4.9 Hz, 3H), 7.28-7.24 (m, 2H), 7.17 (d, J=6.8 Hz, 1H), 7.14 (d, J=5.9Hz, 2H), 6.73 (s, 3H), 4.19 (t, J=6.1 Hz, 2H), 3.00 (t, J=5.9 Hz, 2H),2.52 (quintet, J=8.1 Hz, 4H), 2.35 (s, 3H), 1.61-1.46 (m, 10H),1.34-1.25 (m, 2H); MS (ES) m/e 528 (M+1).

Example 31F2-{3-Butyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)-2-methylpropionicacid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=7.8, 2.4 Hz, 2H), 7.45-7.40 (m,3H), 6.74-6.69 (m, 3H), 4.19 (t, J=6.1 Hz, 2H), 3.00 (t, J=6.1 Hz, 2H),2.51 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.52 (s, 6H), 1.46 (q, J=7.5 Hz,2H), 1.29 (q, J=7.3 Hz, 2H), 0.86 (t, J=7.3 Hz, 3H); MS (ES) m/e 438(M+1).

Example 31G{3-Butyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)acetic acid

¹H NMR (400 MHz, CDCl₃) δ 7.96 (dd, J=7.8, 2.9 Hz, 2H), 7.45-7.40 (m,3H), 6.76 (d, J=3.4 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.63 (dd, J=8.8,2.9 Hz, 1H), 4.57 (s, 2H), 4.14 (t, J=6.4 Hz, 2H), 3.00 (t, J=6.1 Hz,2H), 2.52 (t, J=7.8 Hz, 2H), 2.38 (s, 3H), 1.45 (q, J=7.8 Hz, 2H), 1.28(q, J=7.3 Hz, 2H), 0.85 (t, J=7 Hz, 3H); MS (ES) m/e 410 (M+1).

Example 31H2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-3-phenethylphenoxy}propionicacid)

¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J=4.9 Hz, 2H), 7.42-7.40 (m, 3H),7.26-7.22 (m, 2H), 7.15 (t, J=6.6 Hz, 1H), 7.08 (d, J=7.3 Hz, 2H), 6.75(s, 2H), 6.63 (s, 1H), 4.22 (t, J=6.4 Hz, 2H), 3.00 (t, J=6.4 Hz, 2H),2.86-2.79 (m, 4H), 2.33 (s, 3H), 1.43 (s, 6H), MS (ES) m/e 486 (M+1).

Example 31I2-{3-Cyclohexylmethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid

¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=5.6, 2.7 Hz, 2H), 7.45-7.38 (m,3H), 6.74 (d, J=2.0 Hz, 2H), 6.69 (d, J=2.0 Hz, 1H), 4.20 (t, J=6.1 Hz,2H), 2.99 (t, J=6.4 Hz, 2H), 2.40-2.34 (m, 5H), 1.60-1.51 (m, 10H),1.46-1.39 (m, 1H), 1.30-1.27 (m, 2H), 1.08-1.06 (m, 2H), 0.98-0.82 (m,2H), MS (ES) m/e 478 (M+1).

Example 31J2-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)ethoxy]phenoxy)-2-methyl-propionicacid

¹H NMR (400 MHz, CDCl₃) δ 6.85 (d, 2H, J=8.8 Hz), 6.74 (d, 2H, J=9.3Hz), 4.11 (t, 2H, J=6.1 Hz), 2.97 (t, 2H, J=5.9 Hz), 2.31 (s, 3H),1.99-2.29 (m, 2H), 1.78-1.81 (m, 2H), 1.68-1.71 (m, 1H), 1.48-1.59 (m,3H), 1.47 (s, 6H), 1.21-1.39 (m, 3H), MS (ES) m/e 388.4 (M+1).

Example 322-{2-Benzyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid

Step A 4-Benzyloxy-2-(hydroxy-phenyl-methyl)-phenol

A solution of phenol (Kappe, T.; Witoszynskyj, T. Arch. Pharm., 1975,308 (5), 339-346) (1.14 g, 5.00 mmol) in THF (15 mL) was cooled in a dryice/acetone bath and treated dropwise with phenyllithium (7.5 mL, 13.5mmol, 1.8M in cyclohexane/ethyl ether 70/30). The reaction mixture wasallowed to warm gradually to ambient temperature. After 18 h, thereaction was quenched with aqueous saturated NH₄Cl solution (1 mL) andpartitioned between EtOAc (50 mL) and 1N HCR (20 mL). The organic layerwas washed with brine (75 mL), dried (Na₂SO₄), and concentrated to abrown oil (2.3 g). The crude product was purified by flashchromatography using hexanes:ethyl acetate (3:1 to 2:1) to give a paleyellow oil (1.42 g, 93%): ¹H NMR (400 MHz, CDCl₃) δ 2.79 (s, 1H), 4.92(s, 2H), 5.95, (s, 1H), 6.51 (s, 1H), 6.81 (d, 3H, J=1.5 Hz), 7.28-7.38(s, 10H); MS (ES) m/e 305 [M−1].

Step B2-[4-Benzyloxy-2-(hydroxy-phenyl-methyl)-phenoxy]-2-methyl-propionicacid ethyl ester

4-Benzyloxy-2-(hydroxy-phenyl-methyl)-phenol (690 mg, 2.25 mmol) andCs₂CO₃ (734 mg, 2.25 mmol) in DMF (7 mL) was treated with ethylbromoisobutyrate (0.66 mL, 4.5 mmol) and heated at 55° C. for 16 h.Additional bromo ester (0.40 mL, 1-23 mmol) and Cs₂CO₃ (400 mg, 1.23mmol) were added and the reaction mixture was heated for 40 h. Themixture was cooled and partitioned between EtOAc (30 mL) and H₂O (10mL). The organic layer was washed with brine (10 mL), dried (Na₂SO₄),and concentrated. The crude product was purified by flash chromatographyusing hexanes:ethyl acetate to give a pale yellow oil (615 mg, 65%): ¹HNMR (400 MHz, CDCl₃) δ 1.21 (t, 3H, J=7.3 Hz), 1.39 (s, 3H), 1.43 (s,3H), 4.19 (q, 2H, J=7.3 Hz), 4.97 (s 2H), 6.00 (s, 1H), 6.61 (d, 1H,J=8.8 Hz), 6.74 (dd, 2H, J=3.2, 9.0 Hz), 6.96 (d, 1H, J=2.9 Hz),7.22-7.39 (m, 10).

Step C 2-(2-Benzyl-4-hydroxy-phenoxy)-2-methyl-propionic acid ethylester

A solution of2-[4-benzyloxy-2-(hydroxy-phenyl-methyl)-phenoxy]-2-methyl-propionicacid ethyl ester (1.67 g, 3.97 mmol maximum) in ethanol (50 mL) wastreated with 5% Pd/C (0.42 g) and hydrogen (60 psi, rt, 18 h). Themixture was filtered and concentrated to a viscous colorless oil (1.15g, 91%): ¹H NMR (400 MHz, CDCl₃) δ 1.32 (t, 3H, J=7.1 Hz), 1.51 (s, 6H),3.99 (s, 2H), 4.30 (q, 2H, J=7.0 Hz), 4.93 (brs, 1H), 6.58-6.66 (m, 3H),7.22-7.34 (m, 5H); MS (ES) m/e 315 [M+1].

Step D2-{2-Benzyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)-2-methylpropionicacid ethyl ester

A mixture of 2-(2-benzyl-4-hydroxy-phenoxy)-2-methyl-propionic acidethyl ester (1.14 g, 3.63 mmol), toluene-4-sulfonic acid2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (Japan Tobacco Inc WO9518125) (1.68 g, 4.71 mmol), and Cs₂CO₃ (1.77 g, 5.45 mmol) was heatedat 55° C. in DMF (10 mL) for 72 h. The reaction mixture cooled andpartitioned between EtOAc (30 mL) and H₂O (10 ml). The organic layer waswashed with brine (15 mL). The organic layer was dried (Na₂SO₄) andconcentrated. The crude product was purified by flash chromatographyusing hexanes:ethyl acetate (8:1) to give an oil (1.2 g, 66%): ¹H NMR(400 MHz, CDCl₃) δ 7.96 (dd, 2H, J=7.8, 2.9 Hz), 7.45-7.37 (m, 3H),7.26-7.37 (m, 5H), 6.66 (s, 1H), 6.65 (d, 2H, J=1.5 Hz), 4.23 (q, 2H,J=7.1 Hz), 4.14 (t, 2H J=6.8 Hz), 3.94 (s, 2H), 2.91 (t, 2H, J=6.6 Hz),2.33 (s, 3H), 1.42 (s, 6H), 1.25 (t, 3H, J=7.1 Hz); MS (ES) m/e 500[M+1].

The following compound was prepared by the same procedure:

2-{2-Benzyl-4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionicacid ethyl ester, MS (ES) m/e 506 (M+1).

Step E2-{2-Benzyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid

A solution of2-{2-benzyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid ethyl ester (1.15 g, 2.30 mmol) in THF (15 mL) and MeOH (30 mL) wastreated with 2.5N aqueous NaOH (10 mL). The solution was heated at 55°C. for 2 h, cooled to ambient temperature, and concentrated in vacuo.The residue was acidified with 5N aqueous HCl (5 mL) and partitionedbetween EtOAc (125 mL) and H₂O (25 mL). The organic layer was washedwith brine (50 mL), dried (Na₂SO₄), and concentrated to a colorless oil(1.1 g, 100%): ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, 2H, J=7.6, 2.2 Hz),7.44-7.40 (m, 3H), 7.27-7.15 (m, 5H), 6.77 (d, 1H, J=8.8 Hz), 6.69 (d,1H, J=2.9 Hz), 6.62 (dd, 1H, J=8.8, 2.9 Hz), 4.12 (t, 2H, J=6.4 Hz),3.93 (s, 2H), 2.96 (t, 2H, J=6.6 Hz), 2.35 (s, 3H), 1.45 (s, 6H); MS(ES) m/e 472 [M+1]

The following compound was prepared by the same procedure from theircorresponding ester:

Example 32A2-{2-Benzyl-4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionicacid

¹H NMR (400 MHz, CDCl₃) δ 7.22-7.24 (m, 2H), 7.10-7.17 (m, 3H), 6.75 (d,1H, J=8.8 Hz), 6.64 (d, 1H, J=2.9 Hz), 6.61 (dd, 1H, J=8.8 Hz, J=9.9Hz), 4.08 (t, 2H, J=5.9 Hz), 3.90 (s, 2H), 2.96 (t, 2H, J=6.1 Hz), 2.30(s, 3H), 2.02 (m, 2H), 1.81 (m, 2H), 1.71 (m, 1H), 1.48-1.60 (m, 2H),1.44 (s, 6H), 1.23-1.40 (m, 4H), MS (ES) m/e 478.3 (M+1).

Example 332-{4-Butyl-3-[2-(5-methyl-1-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid

Step A 5-Benzyloxy-2-but-1-enylphenol

To a flame dried 500 mL 3-neck flask under an atmosphere of argon, wascharged n-propyltriphenyl-phosphonium bromide (12.66 g, 32.85 mmol)dissolved in anhydrous THF (85 mL), followed by the dropwise addition ofn-butyllithium 16.4 mL, 26.28 mmol). The dark red mixture was stirred atambient temperature for 1 h. 15 min. Next4-benzyloxy-2-hydroxybenzaldehyde (1.5 g, 6.57 mmol) (Synth. Commun.,26(3), 593-601, (1996) was added followed by the addition of anhydrousdichloromethane (27 mL). The mixture was stirred at ambient temperaturefor 18 h. The solvents were removed in vacuo, and the residue waspartitioned between EtOAc and water (500 mL each). The organic layer waswashed with brine (500 mL), dried (Na₂SO₄), and concentrated in vacuo.The crude product was purified using the Biotage FlashElutechromatography system using a 65M normal phase cartridge, eluting with15% EtOAc/Hex to give a yellow solid (1.50 g, 90%). 2H NMR (400 MHz,CDCl₃) δ 7.43-7.30 (m, 5H), 7.19 (d, J=8.3 Hz, 1H), 6.52 (dd, J=8.8, 2.4Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.43 (s, 1H), 6.14-6.07 (m, 1H), 5.03(s, 2H), 4.98 (s, 1H), 2.25 (quintet, J=7.6 Hz, 2H), 1.09 (t, J=7.3 Hz,3H), MS (ES) m/e 255 (M+1).

Step B4-[2-(5-Benzyloxy-2-but-1-enylphenoxy)ethyl]-5-methyl-2-phenyloxazole

A mixture of 5-benzyloxy-2-but-1-enylphenol (0.090 g, 0.35 mmol),toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester(0.164 g, 0.46 mmol) and cesium carbonate (0.173 g, 0.53 mmol) inanhydrous DMF (0.5 mL) was heated for 18 h at 55° C. The mixture wasconcentrated in vacuo, and the residue was partitioned between EtOAc (60mL) and water (40 mL), washed with brine (50 mL), dried (Na₂SO₄), andremoved in vacuo to give a crude oil which was purified using radialchromatography eluting with 5% EtOAc/Hex to give a white solid (0.11 g,72%). ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=6.8, 2.9 Hz, 2H), 7.44-7.25(m, 9H), 6.58-6.50 (m, 3H), 6.13-6.06 (m, 1H), 5.03 (s, 2H), 4.24 (t,J=6.6 Hz, 2H), 3.00 (t, J=6.4 Hz, 2H), 2.38 (s, 3H), 2.20 (quintet,J=7.2 Hz, 2H), 1.06 (t, J=7.3 Hz, 3H).

Step C 4-Butyl-3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenol

A solution of4-[2-(5-benzyloxy-2-but-1-enylphenoxy)ethyl]-5-methyl-2-phenylox (0.15g, 0.34 mmol) in ethanol (10 mL) was treated with 5% Pd/C (30 mg) undera balloon containing hydrogen at ambient temperature for 24 h. Themixture was filtered and concentrated in vacuo to give a white solid(0.12 g, quantitative). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (dd, J=7.8, 2.0Hz, 2H), 7.44-7.39 (m, 3H), 6.91 (d, J=6.9 Hz, 1H), 6.42 (d, J=2.4 Hz,1H), 6.32 (dd, J=7.8, 2.4 Hz, 1H), 5.54 (br s, 1H), 4.19 (t, J=6.4 Hz,2H), 2.97 (t, J=6.4 Hz, 2H), 2.47 (t, J=7.6 Hz, 2H), 2.39 (s, 3H), 1.43(quintet, J=7.5 Hz, 2H), 1.28 (sextet, J=7.3 Hz, 2H), 0.86 (t, J=7.3 Hz,3H).

Step D2-{4-Butyl-3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid ethyl ester

A mixture of 4-butyl-3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenol(0.11 g, 0.313 mmol), ethyl bromoisobutyrate (0.18 mL, 1.2-5 mmol) andcesium carbonate (0.41 g, 1.25 mmol) in anhydrous DMF (2 mL) was heatedfor 18 h at 55° C. The mixture was concentrated in vacuo, and theresidue was partitioned between EtOAc (50 mL) and water (40 mL), washedwith brine, dried (Na₂SO₄), and removed in vacuo to give a crude oilwhich was purified using radial chromatography eluting with 5-15%EtOAc/Hex to give a yellow oil (0.12 g, 68%). ¹H NMR (400 MHz, CDCl₃) δ7.97 (dd, J=7.6, 1.7 Hz, 2H), 7.45-7.39 (m, 3H), 6.90 (d, J=7.8 Hz, 1H),6.45 (d, J=2.4 Hz, 1H), 6.29 (dd, J=8.3, 2.0 Hz, 1H), 4.25-4.17 (m, 4H),2.97 (t, J=6.4 Hz, 2H), 2.47 (t, J=7.6 Hz, 2H), 2.37 (s, 3H), 1.56 (s,6H), 1.43 (quintet, J=7.7 Hz, 2H), 1.30-1.22 (m, 5H), 0.86 (t, J=7.3 Hz,3H), MS (ES) m/e 466 (M+1).

Step E2-{4-Butyl-3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid

A solution of2-{4-butyl-3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid ethyl ester (0.12 g, 0.258 mmol) in ethanol (3 mL) was treated with2 N aqueous NaOH (0.64 mL), and heated at 55° C. for 8 h. The reactionwas cooled to ambient temperature and concentrated down to near dryness.The residue was then diluted with EtOAc (25 mL) and water (20 mL) andacidified to pH=1 with 1N aqueous HCl. The organic layer was washed withbrine (20 mL), dried (Na₂SO₄) and concentrated in vacuo to give a whitesolid (0.10 g, 88%). ¹H NMR (400 MHz, CDCl₃) δ 7.99-7.97 (m, 2H), 7.00(d, J=7.8 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 6.49 (dd, J=8.3, 2.0 Hz, 1H),4.23 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.52 (t, J=7.6 Hz, 2H),2.38 (s, 3H), 1.59 (s, 6H), 1.50 (quintet, J=7.8 Hz, 2H), 1.32 (sextet,J=7.5 Hz, 2H), 0.90 (t, J=7.3 Hz, 3H), MS (ES) m/e 438 (M+1).

Example 342-{2-Butyl-5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid (507310)

Step A 2-(5-Benzyloxy-2-but-1-enylphenoxy)-2-methylpropionic acid ethylester

5-Benzyloxy-2-but-1-enylphenol (0.70 g, 2.75 mmol) was dissolved inanhydrous DMF (12 mL), followed by the addition of ethylbromoisobutyrate (1.62 mL, 11.0 mmol), and cesium carbonate (3.58 g,11.0 mmol). The mixture was then heated for 18 h (55° C.). The reactionmixture was then cooled and concentrated in vacuo. The crude residue waspartitioned between EtOAc (70 mL) and water (40 mL). The organic layerwas washed with brine, dried (Na₂SO₄), and removed in vacuo. The cruderesidue was purified using radial chromatography, eluting with 5%EtOAc/Hex to give 0.77 g (76%) of a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.41-7.28 (m, 6H), 6.65-6.59 (m, 2H), 6.40 (d, J=2.4 Hz, 1H),6.14-6.07 (m, 1H), 4.99 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 2.22 (quintet,J=7.6 Hz, 2H), 1.56 (s, 6H), 1.26 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.6 Hz,3H), MS (ES) m/e 369 (M+1).

Step B 2-(2-Butyl-5-hydroxyphenoxy)-2-methylpropionic acid ethyl ester

A solution of 2-(5-Benzyloxy-2-but-1-enylphenoxy)-2-methylpropionic acidethyl ester (0.76 g, 2.06 mmol) in ethanol (50 mL) was treated with 5%Pd/C (0.10 g) and hydrogen (60 psi) at ambient temperature for 6 h. Themixture was filtered and concentrated in vacuo to give a colorless oil(0.52 g, 90%). ¹H NMR (400 MHz, CDCl₃) δ 6.96 (d, J=7.8 Hz, 1H), 6.37(dd, J=8.3, 2.4 Hz, 1H), 6.20 (s, 1H), 4.66 (br s, 1H), 4.24 (q, J=7.2Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 1.60 (s, 6H), 1.53 (quintet, J=7.6 Hz,2H), 1.34 (sextet, J=7.3 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.3Hz, 3H), MS (ES) m/e 281 (M+1).

Step C2-{2-Butyl-5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid

The following example exemplifies the general procedure for the parallelsynthesis of analogs utilizing the DynaVac carousel. To a 50 mL glasstube with screw cap and nitrogen inlet were charged2-(2-butyl-5-hydroxyphenoxy)-2-methylpropionic acid ethyl ester, (0.050g, 0.178 mmol), toluene-4-sulfonic acid2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester (0.067 g, 0.187 mmol), andpowdered potassium carbonate (0.050 g, 0.36 mmol) in 1 mL of absoluteethanol. The mixture was heated to reflux for 18 h. MS analysis of thereaction indicated that2-{2-Butyl-5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid ethyl ester, MS (ES) m/e 466 (M+1) had formed. Next 0.4 mL of 5Nsodium hydroxide was added and the reaction was heated for 3 h at 55° C.The ethanol was removed in vacuo and the residue was treated with 1 mLof 5N hydrochloric acid and 1 mL of dichloromethane and poured into a 3mL ChemElute column to remove the aqueous layer. The column was elutedwith additional dichloromethane until nothing UV active remained on thecolumn. The solvent was removed in vaco. The crude residue was purifiedby mass-directed reverse phase HPLC to provide 0.038 g (49%) of2-{2-Butyl-5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)-2-methylpropionicacid, ¹H NMR (400 MHz, CDCl₃) δ 7.99 (dd, J=6.4, 2.4 Hz, 2H), 7.46 (dd,J=5.9, 2.4 Hz, 3H), 7.03 (d, J=8.3 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.51(dd, J=8.3, 2.4 Hz, 1H), 4.18 (t, J=7.3 Hz, 2H), 2.95 (t, J=7.3 Hz, 2H),2.54 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.63 (s, 6H), 1.53 (quintet, J=7.6Hz, 2H), 1.35 (sextet, J=7.3 Hz, 2H), 0.92 (t, J=7.1 Hz, 3H), MS (ES)m/e 438 (M+1). The following compounds were also prepared by thisprocedure:2-{2-Butyl-5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)-2-methylpropionicacid ethyl ester, MS (ES) m/e 472 (M+1). Example 34A:2-{2-Butyl-5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid

¹H NMR (400 MHz, CDCl₃) δ 6.98 (d, J=8.3 Hz, 1H), 6.43 (dd, J=7.1, 2.4Hz, 1H), 6.39 (d, J=2.4 Hz, 1H), 4.18 (t, J=5.9 Hz, 2H), 3.06-3.00 (m,1H), 2.96 (t, J=6.1 Hz, 2H), 2.51 (t, J=7.6 Hz, 2H), 2.33 (s, 3H),2.08-2.05 (m, 2H), 1.86-1.82 (m, 2H), 1.75-1.72 (m, 1H), 1.63-1.40 (m,10H), 1.37-1.25 (m, 5H), 0.92 (t, J=7.3 Hz, 3H), MS (ES) m/e 444 (M+1).

2-(5-[2-(2-Cyclohexyl-5-methyloxazol-4-yl)ethoxy]-2-propylphenoxy)-2-methylpropionicacid ethyl ester, MS (ES) m/e 558 (M+1). Example 34B:2-{5-[2-(2-Cyclohexyl-5-methyloxazol-4-yl)ethoxy]-2-propylphenoxy)-2-methylpropionicacid

¹H NMR (400 MHz, CDCl₃) δ 6.98 (d, J=8.3 Hz, 1H), 6.43 (d, J=7.3 Hz,2H), 4.17 (t, J=6.1 Hz, 2H), 3.02-2.99 (m, 1H), 2.93 (t, J=5.9 2H), 2.31(s, 3H), 2.18-2.05 (m, 2H), 1.85-1.87 (m, 2H), 1.75-1.72 (m, 1H),1.63-1.51 (m, 9H), 1.43-1.26 (m, 4H), 0.91 (t, J=7.1 Hz, 3H), MS (ES)m/e 430 (M+1).

2-Methyl-2-{5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-propylphenoxy)propionicacid ethyl ester, MS (ES) m/e 452 (M+1).

Example 34C2-Methyl-2-{5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-propylphenoxy}propionicacid

¹H NMR (400 MHz, CDCl₃) δ 8.01-7.98 (m, 2H), 7.49-7.46 (m, 3H), 7.02 (d,J=8.3 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.3, 2.4 Hz, 1H),4.19 (t, J=7.3 Hz, 2H), 2.97 (t, J=7.3 Hz, 2H), 2.39 (s, 3H), 1.62 (s,6H), 1.58 (sextet, J=7.3 Hz, 2H), 0.93 (t, J=7.6 Hz, 3H), MS (ES) m/e424 (M+1).

Example 352-Methyl-2-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionicacid

Step A (5-methyl-2-phenyl-thiazol-4-yl)-acetic acid methyl ester

Thiobenzamide (7.3 g) in toluene was heated at reflux for 1 h in a flaskequipped with a Dean-Stark trap. After 1.2 mL water was obtained, thedry thioamide (6.0 g, 28 mmol) and 4-bromo-3-oxo-pentanoic acid methylester (9.0 g, 43 mmol) were heated in toluene (200 mL) for 3 h. Thecooled reaction was concentrated and purified by short pathchromatrography (400 g silica gel, 15% EtOAc/hexanes, then 20%EtOAc/hexanes). The fractions that contained pure product wereconcentrated to yield 3.53 g (39%) ester as a yellow oil: ¹H NMR (CDCl₃)δ 2.40 (s, 3H), 3.70 (s, 3H), 3.78 (s, 2H), 7.34-7.39 (m, 3H), 7.85 (d,2H); MS (m/e) 248 (M+H).

Step B 2-(5-Methyl-2-phenyl-thiazol-4-yl)-ethanol

According to the general method of Collins et al, J. Med. Chem. 415037-5054 (1998), a THF (100 mL) solution of2-(5-methyl-2-phenyl-thiazol-4-yl)-acetic acid methyl ester (3.5 g, 16mmol) was cooled to 0° C. and a 1M LiAlH₄ (16 mL, 16 mmol) was addedslowly. After stirring at room temperature for 45 min, tlc (15%EtOAc/hexane) showed that all the starting ester had been consumed. Thereaction was cooled and carefully quenched with 4 mL water, 2.6 mL 5NNaOH and 2 mL water. The light tan solid was filter and dried to give3.29 g crude product. Recrystallization (60 mL toluene) gave 2.36 g(50%) alcohol as a light tan oil: ¹H NMR (CDCl₃) δ 2.42 (s, 3H), 2.94(t, 2H), 4.03 (t, 2H), 7.39-7.47 (m, 3H), 7.85-7.93 (m, 2H)

Step C2-Methyl-2-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenoxy}-propionicacid ethyl ester

As described in Example 9, Part E,2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol (2.0 g, 6.77 mmol) wasconverted to the tosylate derivative 2.87 g (94%) with a crude product(MS (m/e) 375 (MH)) and used without further purification. A mixture oftoluene-4-sulfonic acid 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethyl ester(2.8 g, 6.2 mmol), .Cs₂CO₃ (1.8 g, 5.5 mmol) phenol (1.0 g, 4.4 mmol) inDMF (100 mL) was warmed at 55° C. for 18 h. The reaction was partitionedbetween EtOAc/water. The organic solution was washed a second time withwater and then dried (MgSO₄). After concentration, 3.2 g crude productwas obtained. Purification by flash column chromatography (15%EtOAc/hexane) gave 420 mg (19%) ester as a colorless oil:

Toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethyl ester,90% as a white semi-solid: ¹H NMR (CDCl₃) δ 2.24 (s, 3H), 2.40 (s, 3H),3.07 (t, 2H), 4.42 (t, 2H), 7.18 (d, 2H), 7.35-7.47 (m, 3H), 7.66 (d,2H), 7.75-7.84 (m, 2H); MS (m/e) 374 (M+H).

2-Methyl-2-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenoxy}-propionicacid ethyl ester 19% yield as a colorless oil: ¹H NMR (CDCl₃) δ 1.31 (t,3H), 1.54 (s, 6H), 2.47 (s, 3H), 3.22 (t, 2H), 4.27 (q, 2H), 4.31 (t,2H), 6.78-6.88 (m, 4H), 7.40-7.45 (m, 3H), 7.87-7.94 (m, 2H); MS (m/e)426 (M+H).

Step D2-Methyl-2-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionicacid

A sample of ester (400 mg, 0.8 mmol) was dissolved in EtOH (15 mL) and5N NaOH (5 mL) added. The reaction was warmed at 40° C. for 1.5 h andthen cooled to room temperature. After removing some of the EtOH, thereaction was acidified with HCl. After stirring in an ice-bath for 1 h,the yellow solid was collected and dried to give 328 mg (76%) yield as apale yellow solid: mp 163.5° C.; ¹H NMR (CDCl₃) δ 1.53 (s, 6H), 2.49 (s,3H), 3.24 (t, 2H), 4.32 (t, 2H), 6.82-6.95 (m, 4H), 7.40-7.47 (m, 3H),7.88-7.95 (m, 2H); MS (m/e) 398 (M+H).

Example 362-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethylsulfanyl]phenoxy}propionicacid

Step A 2-(4-Dimethylthiocarbamoyloxy-phenoxy)-2-methyl-propionic acidethyl ester

A DMF (100 mL) solution of 2-(4-hydroxyphenoxy)-2-methyl propionic acidethyl ester (15.2 g, 67.7 mmol) and DABCO (15.2 g, 135.5 mmol) wascharged dropwise with N,N-dimethylthiocarbamoyl chloride (16.7 g, 135.5mmol) in 20 mL DMF over 15 min. The reaction was stirred at rt for 18 hand then quenched with water. The reaction was partitioned between water(1L) and EtOAc (500 mL) and the organic layer washed with 1N HCl (500mL). After drying (MgSO₄) and concentration, the crude product wasobtained as a tan oil. Purification by flash chromatography (15%EtOAc/hexane) provided the product (15.8 g, 75%) as a pale yellow oil:¹H NMR (CDCl₃) δ 1.32 (t, 3H), 1.65 (s, 6H), 3.37 (s, 3H), 3.50 (s, 3H),4.30 (q, 2H), 6.93 (dd, 4H); MS (m/e) 312.

Step B 2-(4-Dimethylcarbamoylsulfanyl-phenoxy)-2-methyl-propionic acidethyl ester

Neat (2-(4-dimethylthiocarbamoyloxyphenoxy)-2-methyl propionic acidethyl ester (15 g, 48.2 mmol) was heated at 200° C. for 1 h. TLC (20%EtOAc/hexane) showed that no reaction had occurred. The temperature wasraised to 240° C. for 30 min. By TLC, all starting material was gone andthere was significant decomposition. Purification by short plug column(20% EtOAc/hexane) followed by prep HPLC gave the product (2.6 g) as apale yellow oil: ¹H NMR (CDCl₃) δ 1.27 (t, 3H), 1.63 (s, 6H), 3.05 (brs, 6H), 4.24 (q, 2H), 6.86 (d, 2H), 7.35 (d, 2H); MS (m/e) 312.

Step C2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethylsulfanyl]phenoxy}propionicacid ethyl ester

Freshly prepared NaOEt (from 50 mg (2.2 mmol) Na) was charged with2-(4-dimethylcarbamoylsulfanyl-phenoxy)-2-methyl-propionic acid ethylester (420 mg, 1.35 mmol) and refluxed for 3 h. Toluene-4-sulfonic acid2-(5-methyl-2-phenyloxazol-4-yl)-ethyl ester (572 mg, 2.2 mmol) wasadded and the mixture was refluxed for another 3 h. The reaction wascooled and concentrated. The residue was shaken with EtOAc/water. Aftera second water wash, the organic layer was dried (MgSO₄) andconcentrated to give 500 mg crude product. Purification by flashchromatography (15% EtOAc/hexane) provided the product (98 mg, 17%):R_(f)=0.32 in 15% EtOAc/hexane; MS m/e 426 (1H⁺).

Step D2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethylsulfanyl]phenoxy)propionicacid

2-Methyl-2-(4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethylsulfanyl]phenoxy}propionicacid ethyl ester (98 mg, 0.23 mmol) was dissolved in EtOH (10 mL) and 5NNaOH (0.5 mL) was added. The reaction was stirred overnight at rt. Thereaction was acidified with 5N HCl and the product was extracted intoEtOAc, dried (MgSO₄) and concentrated to give 96 mg crude product.Purification by reverse phase HPCL gave 47.5 mg (52%) as a light tansolid: mp 104-106° C., ¹H NMR (DMSO-d₆) δ 1.47 (s, 6H), 2.26 (s, 3H),2.71 (t, 2H), 3.16 (t, 2H), 6.78 (d, 2H), 7.30 (d, 2H), 7.48 (m, 3H),7.90 (m, 2H), 13.08 (br s, 1H).

Example 372-Methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yloxy}-propionicacid

Step A 2-(4-Hydroxy-naphthalen-1-yloxy)-2-methyl-propionic acid ethylester

A solution of naphthalene-1,4-diol (30.0 g, 187 mmol) was prepared inDMF (60 mL, anhydrous), cooled to 0° C., and treated with NaH (7.50 g ofa 60% solution in oil, 188 mmol) in portions, over a 5 min period. Theice bath was removed and the mixture stirred for 30 min. The resultingblack suspension was treated with ethyl 2-bromoisobutyrate (27.6 mL, 188mmol) and stirred at 95° C. for 18 h. The mixture was cooled to rt, thenpoured into cracked ice containing HCl (1 N aqueous, 200 mL). Theaqueous layer was extracted with ethyl ether (3×500 mL) and the organiclayers washed with brine (100 mL), dried (MgSO₄), filtered, and thefiltrate evaporated (40° C., 20 mm Hg). The residue was chromatographedon SiO₂ (Biotage, 65M column; 18% EtOAc/hexanes) to afford a total of19.2 g of 2-(4-hydroxy-naphthalen-1-yloxy)-2-methyl-propionic acid ethylester as a black oil 37% yield: R_(f)=0.31 (20% EtOAc/hexanes); ¹H NMR(CDCl₃) δ 8.2 (m, 1H), 8.1 (m, 1H), 7.5 (m, 2H), 6.62 (dd, J=15.4, 8.4Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 1.60 (s, 6H), 1.21 (t, J=7.2 Hz, 3H);MS (ES+) m/e (% relative intensity) 275.1 (M⁺+1, 21), 230.1 (33), 229.0(100), 201.0 (60).

Step B2-Methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yloxy}-propionicacid ethyl ester

A solution of 2-(4-hydroxy-naphthalen-1-yloxy)-2-methyl-propionic acidethyl ester (450 mg, 1.64 mmol) and toluene-4-sulfonic acid2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (700 mg, 1.96 mmol) wasprepared in DMF (4 mL, anhydrous) under N₂, treated with Cs₂CO₃ (638 mg,1.96 mmol), and stirred at 60° C. for 18 h. The solution was poured into1/1H₂O/brine and extracted twice with 2/1 EtOAc/toluene. The organiclayers were washed with brine, dried (MgSO₄), filtered, and the filtrateevaporated (40° C., 20 mm Hg) to a residue. The residue waschromatographed on SiO₂ (Biotage, 40L column; 20% EtOAc/hexanes) toafford 440 mg of2-methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yloxy}propionicacid ethyl ester as a colorless solid, 58% yield: ¹H N (400 MHz, CDCl₃)δ 8.1 (m 2H), 7.94 (dd, J=8.0, 1.6 Hz, 2H), 7.4 (m, 5H), 6.68 (d, J=8.6Hz, 1H), 6.62 (d, J=8.6 Hz, 1H), 4.33 (t, J=6.4 Hz, 2H), 4.21 (q, J=7.2Hz, 2H), 3.06 (t, J=6.4 Hz, 2H), 2.36 (s, 3H), 1.59 (s, 6H), 1.20 (t,J=7.2 Hz, 3H); MS (ES+) m/e (% relative intensity) 462.2 (16), 461.2(72), 460.1 (M⁺+1, 100).

Step C2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]naphthalen-1-yloxy}propionicacid

A solution of2-methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yloxy}-propionicacid ethyl ester (440 mg, 91 μmol) was prepared in THF (10 mL) andmethanol (2 mL), treated with NaOH (2.0 mL of a 1 N aqueous solution,2.0 mmol), and stirred for 4 h. The solution was acidified with HCl (400μL, 5 N aqueous, 2.0 mmol), and partitioned between water and EtOAc. Thelayers were separated and the organic layer dried (MgSO₄), filtered, andthe filtrate evaporated (40° C., 20 mm Hg). The residue was trituratedwith ethyl ether to afford 260 mg (2 crops) of2-methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yloxy}-propionicacid as a pink powder, 63% yield: ¹H NMR (400 MHz, CDCl₃) δ 8.1 (m 2H),8.00 (d, J=8.8 Hz, 2H), 7.4 (m, 5H), 6.87 (d, J=8.4 Hz, 1H), 6.58 (d,J=8.4 Hz, 1H), 4.27 (t, J=6.1 Hz, 2H), 3.12 (t, J=6.1 Hz, 2H), 2.42 (s,3H), 1.62 (s, 6H); MS (ES⁺) m/e (% relative intensity) 433.2 (50), 432,1.20 (t, J=7.2 Hz, 3H). 2 (M⁺+1, 100).

Example 382-Methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-propionicacid

Step A 5,6,7,8-Tetrahydronaphthalene-1,4-diol

A solution of naphthalene-1,4-diol (4.00 g, 25.0 mmol) was prepared inethanol (95 mL) and acetic acid (25 mL), treated with PtO₂ (0.60 g, 2.6mmol), charged with H₂ (60 psig), and shaken for 18 h at 40° C. Thecatalyst was filtered off and the filtrate evaporated (40° C., 20 mm Hg)The residue was dissolved in EtOAc (100 mL) and washed with NaHCO₃(saturated aqueous, 100 mL), brine (100 mL), dried (MgSO₄), filtered,and the filtrate evaporated (40° C., 20 mm Hg) to afford a total of 2.6g of 5,6,7,8-tetrahydro-naphthalene-1,4-diol as a black solid, 63%yield: ¹H NMR (CDCl₃) δ 6.45 (s, 2H), 2.6 (m, 4H), 1.9 (m, 4H); MS (ES+)m/e (% relative intensity) 327.2 (100), 165.1 (M⁺+1, 26).

Step B 2-(4-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yloxy)-2-methylpropionic acid ethyl ester

A solution of 5,6,7,8-tetrahydronaphthalene-1,4-diol (2.60 g, 15.8 mmol)was prepared in DMF (20 mL, anhydrous), cooled to 0° C., and treatedwith NaH (0.63 g of a 60% solution in oil, 15.8 mmol) in one portion.The ice bath was removed and the mixture stirred for 30 min. Theresulting black suspension was treated with ethyl 2-bromoisobutyrate(2.33 mL, 15.9 mmol) and stirred at 100° C. for 18 h. The mixture wascooled to rt, then poured into cracked ice containing HCl (1 N aqueous,20 mL). The aqueous layer was extracted with ethyl ether (3×50 mL) andthe organic layers washed with brine (100 mL), dried (MgSO₄), filtered,and the filtrate evaporated (40° C., 20 mm Hg). The residue waschromatographed on SiO₂ (Biotage, 40L column; 15% EtOAc/hexanes) toafford a total of 1.2 g of2-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2-methyl-propionicacid ethyl ester as a black oil 27% yield: Rf=0.27 (15% EtOAc inhexanes); ¹H NMR (CDCl₃) δ 6.42 (d, J=8.6 Hz, 2H), 6.38 (d, J=8.6 Hz,2H), 4.20 (q, J=7.2 Hz, 2H), 2.61 (t, J=6.0 Hz, 2H), 2.55 (t, J=6.0 Hz,2H), 1.6 (m, 4H), 1.49 (s, 6H), 1.23 (t, J=7.2 Hz, 3H); MS (ES⁺) m/e (%relative intensity) 301.1 (28), 279.2 (M⁺+1, 49), 233.1 (100), 205.1(470), 165.1 (88).

Step C2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-5,6,7,8-tetrahydronaphthalen-1-yloxy}propionicacid ethyl ester

A solution of2-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2-methyl propionicacid ethyl ester (400 mg, 1.44 mmol) and toluene-4-sulfonic acid2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester (608 mg, 1.70 mmol) wasprepared in DMF (4 mL, anhydrous) under N₂, treated with Cs₂CO₃ (555 mg,1.70 mmol), and stirred at 55° C. for 24 h, then stirred over the weekend at rt. The solution was poured into dilute aqueous HCL and extractedtwice with EtOAc. The organic layers were washed with brine, dried(MgSO₄), filtered, and the filtrate evaporated (40° C., 20 mm Hg) to aresidue. The residue was chromatographed on SiO₂ (Biotage, 40S column;15% EtOAc/hexanes) to afford 350 mg of2-methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-5,6,7,8-tetrahydronaphthalen-1-yloxy}propionicacid ethyl ester as a colorless solid, 52% yield: ¹H NMR (400 MHz,CDCl₃) δ 7.92 (dd, J=7.8, 1.8 Hz, 2H), 7.3 (m, 3H), 6.4 (m, 2H), 4.19(q, J=7.0 Hz, 2H), 4.11 (t, J=6.4 Hz, 2H), 2.91 (t, J=6.4 Hz, 2H), 2.6(m, 4H), 2.32 (s, 3H), 1.7 (m, 4H), 1.48 (s, 6H), 1.22 (t, J=7.0 Hz,3H); MS (ES+) m/e (% relative intensity) 466.3 (16), 465.3 (70), 464.3(M⁺+1, 100).

Step D2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-5,6,7,8-tetrahydronaphthalen-1-yloxy}propionicacid

A solution of2-methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-5,6,7,8-tetrahydronaphthalen-1-yloxy}propionicacid ethyl ester (350 mg, 755 μmol) was prepared in THF (10 mL) andmethanol (3 mL), treated with NaOH (3.0 mL of a 1 N aqueous solution,3.0 mmol), and stirred for 18 h. The solution was acidified with HCl(1.0 mL, 5 N aqueous, 5.0 mmol), and partitioned between water andEtOAc. The layers were separated and the organic layer was washed withbrine, dried (MgSO₄), filtered, and the filtrate evaporated (40° C., 20mm Hg). The resulting solid was recrystallized from EtOAc/hexanes toafford 179 mg (2 crops) of2-methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]5,6,7,8-tetrahydro-naphthalen-1-yloxy}-propionicacid as a colorless powder, 54% yield: ¹H NMR (400 MHz, CDCl₃) δ 7.9 (m2H), 7.4 (m, 3H), 6.63 (d, J=8.8 Hz, 1H), 6.50 (d, J=8.8 Hz, 1H), 4.11(t, J=6.0 Hz, 2H), 2.98 (t, J=6.0 Hz, 2H), 2.57 (m, 4H), 2.35 (s, 3H),1.7 (m, 4H), 1.51 (s, 6H); MS (ES+) m/e (% relative intensity) 437.3(52), 436.2 (M⁺+1, 100).

Additional compounds of the present invention, having the structuralformula shown below, were synthesized by similar to those described inthe previous examples.

These additional compounds are further exemplified in the followingtable.

TABLE I Ex. R1 o-R7 m-R7 R9 R10 39A phenyl H H H benzyl 39B phenylpentyl H Me Me 39C phenyl H pentyl Me Me 39D cyclohexyl pentyl H Me Me39E phenyl H H Et Et 39F cyclohexyl butyl H Me Me 39G 2-thienyl H H MeMe 39H 2-thienyl H benzyl Me Me 39I 2-thienyl H C₆H₁₁CH₂ Me Me 39Jphenethyl H H Me Me 39K benzyl H H Me Me 39L phenyl- H H Me Me propyl39M phenethyl H H Me benzyl 39N phenethyl H benzyl Me Me 39O phenethyl HH Me benzyl 39P phenethyl H benzyl Me Me 39Q 2-thienyl H H Me benzyl 39Rphenyl- H H Me benzyl propyl 39S cyclohexyl H H Me benzyl 39T 1-methyl-H H Me benzyl cyclohexyl 39U phenyl H benzoyl Me Me 39V 2-thienyl Hbenzoyl Me Me 39W cyclohexyl H H Me 4-trifluoro- methylbenzyl 39Xcyclohexyl H H Me 4-trifluoro- methyloxybenzyl 39Y cyclohexyl H H Me4-phenyl benzyl 39Z cyclohexyl H H Me 4-trifluoro- methyloxybenzyl 39AAcyclohexyl H H Me 4-methyl benzyl 39BB cyclohexyl H H Me 3-methyl benzyl39CC cyclohexyl H H Me 4-methoxybenzyl 39DD cyclohexyl H H Me3-methoxybenzyl 39EE cyclohexyl H H Me 2-methyl benzyl 39FF cyclohexyl HH Me 4-trifluoro- methylbenzyl 39GG cyclohexyl H H Me 2-methyloxy benzyl39HH cyclohexyl H H Me 2-trifluoro- methylbenzyl

Example 40{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-2-propyl-phenoxy}-aceticacid

Step A (2-Allyl-phenoxy)-acetic acid ethyl ester

A mixture of 2-allyl-phenol (10 g, 74.5 mmol), ethyl 2-bromoacetate(12.4 mL, 112 mmol) and cesium carbonate (36.5 g, 112 mmol) in DMF (180mL) was heated at 60° C. overnight. The mixture was cooled and filteredthrough a pad of celite. The filtrate was diluted with water andextracted with ethyl acetate. The combined organic layers were washedwith water, dried over sodium sulfate, filtered, and concentrated. Thecrude material was purified by column chromatography on silica gel togive 14.5 g of title compound. ¹H NMR (400 MHz, CDCl₃). 7.19-7.14 (m,2H), 6.97-6.92 (m, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.09-5.95 (m, 1H),5.11-5.02 (m, 2H), 4.54 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 3.46 (d, J=6.8Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).

Step B (2-Propyl-phenoxy)-acetic acid ethyl ester

A solution of (2-allyl-phenoxy)-acetic acid ethyl ester (5.8 g, 26.3mmol) in ethanol (200 mL) was treated with 5% Pd/C (59 mg) and hydrogenat ambient temperature for overnight. The mixture was filtered andconcentrated to give the title compound (5.7 g, 98%). ¹H NMR (400 MHz,CDCl₃). 7.16˜7.10 (m, 2H), 6.94˜6.89 (m, 1H), 6.71 (d, J=8.1 Hz, 1H),4.53 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H), 1.71˜1.60(m, 2H), 1.29 (t, J=7.0 Hz, 2H), 0.96 (t, J=7.0 Hz, 3H); MS (ES) m/e406.18 (M⁺+1).

Step C (4-Chlorosulfonyl-2-propyl-phenoxy)-acetic acid ethyl ester

(2-Propyl-phenoxy)-acetic acid ethyl ester (5.0 g, 22.4 mmol) was addedto chlorosulfonic acid (6.6 mL) at 0° C. dropwise. After addition, themixture was warmed to room temperature slowly and stirred for 2 h. Thereaction mixture was poured into ice and stirred for 1 h, filtered andthe solid product was washed with water, dried in vacuum oven over nightgiving the title compound (6.0 g, 83.5%). ¹H NMR (400 MHz, DMSO)-7.35(s, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 4.78 (s, 2H),4.13 (q, J=7.3 Hz, 2H), 2.54 (t, J=7.3 Hz, 2H), 1.60-1.50 (m, 2H), 1.18(t, J=7.3 Hz, 2H), 0.88 (t, J=7.3 Hz, 3H).

Step D (4-Mercapto-2-propyl-phenoxy)-acetic acid ethyl ester

A mixture of (4-chlorosulfonyl-2-propyl-phenoxy)-acetic acid ethyl ester(1.12 g, 3.5 mmol), tin powder (2.1 g) and HCl (4.0 M in dioxane, 4.4mL) in ethanol (4.4 mL) was refluxed for 4 h, the mixture was pouredinto ice, extracted with methylene chloride. The combined organic layerswere washed with brine, dried over sodium sulfate, concentrated to givethe title compound, which was used for next step without purification.

Step E(4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-2-propyl-phenoxy)-aceticacid

To a mixture of (4-mercapto-2-propyl-phenoxy)-acetic acid ethyl ester(127 mg, 0.5 mmol) and4-Chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (131 mg,0.48 mmol) in acetonitrile (2 mL) was added cesium carbonate (326 mg, 1mmol). After 4 h at room temperature, the reaction was quenched bywater, extracted with ethyl acetate. Combined organic layers were washedwith brine, dried (sodium sulfate) and concentrated. The residue wastaken into THF (2 mL) and treated with lithium hydroxide (1N. 0.5 mL) atroom temperature for 2 h. THF was evaporated, the residue was treatedwith water (0.5 mL) and extracted with ether. The aqueous was acidifiedwith 5 N HCl, extracted with ether, dried over sodium sulfate andconcentrated. The crude product was purified by reversed phase HPLC togive the title compound (125 mg, 53.7%)

¹H NMR (400 MHz, DMSO)•8.08 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H),7.15˜7.12 (m, 1H), 7.10˜7.08 (m, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.57 (s,21H), 3.94 (s, 2H), 2.50˜2.42 (m, 2H), 2.00 (s, 3H), 1.52˜1.41 (m, 2H),0.79 (t, J=8.0 Hz, 3H); MS (ES) m/e: 466.07 (M⁺+1).

The following compounds were made in a substantially similar manner

Example 41[4-(5-Methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-2-propyl-phenoxy]-aceticacid

¹H NMR (400 MHz, DMSO)•7.89˜7.85 (m, 2H), 7.49˜7.47 (m, 3H), 7.14 (dd,J=2.4, 8.2 Hz, 1H), 7.1 (d, J=2.3 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.67(s, 2H), 3.92 (s, 21H), 2.55˜2.41 (m, 2H), 1.98 (s, 3H), 1.52˜1.40 (m,2H), 0.81 (t, J=7.2 Hz, 3H); MS (ES) m/e 398.12 (M⁺+1).

Example 42A{4-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-2-propyl-phenoxy}-aceticacid

¹H NMR (400 MHz, DMSO)•12.93 (br, 1H)—, 7.84˜7.78 (m, 2H), 7.47˜7.30 (m,5H), 7.16˜7.08 (m, 4H), 6.75 (d, J=7.9 Hz, 1H), 5.15 (s, 2H), 4.67 (s,2H), 3.89 (s, 2H), 2.50˜2.44 (m, 2H), 1.96 (s, 3H), 1.52˜1.43 (m, 2H),0.81 (t, J=7.8 Hz, 3H); MS (ES) m/e: 504.11 (M⁺+1)

Example 42{4-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-2-propyl-phenoxy}-aceticacid

¹H NMR (400 MHz, DMSO)•12.91 (br, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.59 (d,J=8.4 Hz, 2H), 7.16˜7.11 (m, 1H), 7.10˜7.07 (m, 1H), 6.76 (d, J=8.4 Hz,1H), 4.67 (s, 2H), 3.92 (s, 2H), 2.51˜2.44 (m, 2H), 1.98 (s, 3H),1.53˜1.44 (m, 2H), 0.80 (t, J=8.0 Hz, 3H); MS (ES) m/e: 476.02 (M⁺+1,⁷⁹Br), 478.03 (M⁺+1, ⁸¹Br)

Example 43{4-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenoxy}-aceticacid

¹H NMR (400 MHz, DMSO)•12.91 (br, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.49-7.29(m, 5H), 7.13 (d, J=8.4 Hz, 2H), 6.83 (m, 1H), 6.79-6.71 (m, 2H), 5.15(s, 2H), 4.86 (s, 2H), 4.59 (s, 2-H), 2.38 (s, 3H), 2.16 (s, 3H); MS(ES) m/e: 460.2 (M⁺+1).

Example 44{4-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-phenoxy}-aceticacid

¹H NMR (400 MHz, DMSO)•12.93 (br, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.47-7.25(m, 7H), 7.11 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 5.15 (s, 2H),4.65 (s, 2H), 3.91 (s, 2H), 1.99 (s, 3H); MS (ES) m/e: 462.09 (M⁺+1).

Example 45{4-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenoxy}-aceticacid

¹H NMR (400 MHz, DMSO-d6)•7.85 (d, J=8.8 Hz, 2H), 7.45 (d, J=7.8 Hz,2H), 7.38-7.34 (m, 2H), 7.32-7.30 (m, 1H), 7.13 (d, J B. 8 Hz, 2H), 6.94(d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.15 (s, 2H) 4.88 (s, 2H),4.57 (s, 2H), 2.38 (s, 3H); MS (ES) m/e 446.2 (M⁺+1), 444.1 (M⁺−1).

Example 464-[4-(4-Carboxymethoxy-3-methyl-phenoxyethyl)-5-methyl-oxazol-2-yl]-benzoicacid

¹HNMR (400 MHz, DMSO-d₆)•8.04 (s, 4H), 6.75 (m, 3H), 4.91 (s, 2H), 4.59(s, 2H), 2.43 (s, 3H), 2.16 (s, 3H); ESMS m/e 398.2 (M+H⁺, 100).

Example 47(4-{2-[2-(4-Butoxy-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

¹H NMR (DMSO-d₆, 400 MHz): δ 0.918 (t, J=7.34 Hz, 3H), 1.39-1.45 (m,2H), 1.65-1.76 (m, 2H), 2.13 (s, 3H), 2.22 (s, 3H), 2.65 (t, J=7.09 Hz,2H), 3.10 (t, J=7.09 Hz, 2H), 4.00 (t, J=6.36 Hz, 2H), 4.63 (s, 2H),6.75 (d, J=8.31 Hz, 1H), 7.00 (d, J=9.18 Hz, 2H), 7.13-7.17 (m, 2H),7.77 (d, J=9.28 Hz, 2H), 12.9 (br s, 1H); MS (ES, m/z):C₂₅H₂₉NO₅S:456.2(M⁺+1), 454.1(M⁺−1).

Example 48 Procedure 1

A.2-{2-hydroxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)-2-methylpropionicacid ethyl ester

To a 25 mL round bottom flask under a nitrogen atmosphere were charged0.77 g (2.17 mmol) of toluene-4-sulfonic acid2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester, and 0.5 g (1.97 mmol) of2-(4-hydroxy-2-hydroxymethylphenoxy)-2-methylpropionic acid ethyl esterdissolved in 10 mL of absolute ethanol. Next, 0.54 g (3.94 mmol) ofpotassium carbonate (325 mesh) was added and the reaction was heated to80° C. for 12 h. The volatiles were removed in vacuo and the cruderesidue was dissolved in 75 mL EtOAc and washed twice with brine, driedover Na₂SO₄, and removed in vacuo to give a crude oil. This cruderesidue was purified using radial chromatography with a 2 mm normalphase silica gel plate, eluting with a step gradient of 5:95 EtOAc:Hexto 35:65 EtOAc:Hex to give a colorless oil (0.17 g, 20%). MS (ES) m/e452 (M+1).

B.2-{2-Methoxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy})-2-methylpropionicacid ethyl ester

To a 15 mL round bottom flask under a nitrogen atmosphere were charged0.075 g (0.17 mmol) of2-{2-hydroxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)-2-methylpropionicacid ethyl ester, dissolved in 1 mL of anhydrous DMF, followed by theaddition of 0.16 mL (1.7 mmol) of methyl iodide. The reaction solutionwas cooled down in an ice bath and was treated with 0.014 g (0.34 mmol)of NaH. The reaction was stirred cold for 2 h. Next the reaction waspoured into 6 mL of EtOAc and 10 mL of brine, and then acidified usingdilute sulfuric acid. The organic layer was separated away, dried overNa₂SO₄, and removed in vacuo to give a crude oil. This crude residue waspurified using radial chromatography with a 1 mm normal phase silica gelplate, eluting with 15:85 EtOAc:Hex to give a colorless oil (0.039 g,51%). MS (ES) m/e 454 (M+1).

C.2-{2-Methoxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid

To a 25 mL round bottom flask were charged 0.039 g (0.087 mmol) of2-{2-methoxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy)-2-methylpropionicacid ethyl ester dissolved in 2 mL of ethanol, followed by the additionof 0.22 mL (0.44 mmol) of 2N NaOH. The solution was heated to 55° C. for1 h. The volatiles were removed in vacuo and the residue was taken up in10 mL EtOAc and 5 mL of brine and acidified using 1N HCl to give a whitesolid (0.024 g, 66%) . MS (ES) m/e 426 (M+1).

The following compound was also prepared by this procedure:

Example 49

-   2-{2-Benzyloxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]phenoxy}-2-methylpropionic    acid, MS (ES) m/e 530 (M+1).

Example 50 Procedure 2

A.3-{2-Cyclohexylcarbamoyloxymethyl-4-[2-(2-phenyloxazol-4-yl)ethoxy]phenyl}propionicacid ethyl ester

To a 15 mL round bottom flask under N₂ were charged 0.075 g (0.17 mmol)of2-{2-hydroxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid ethyl ester, and 0.13 mL (1.0 mmol) of cyclohexylisocyanatedissolved in 0.5 mL of anhydrous MeCl₂, followed by the addition of0.086 mL (0.086 mmol) of 1.0 N HCl in ether. The reaction was stirred atRT for 18 h. Next, the reaction was diluted with 10 mL MeCl₂, washedwith brine, dried over Na₂SO₄ and removed in vacuo to give 0.10 g of acrude oil which was used directly in the next step. MS (ES) m/e 564(M+1).

B.3-{2-Cyclohexylcarbamoyloxymethyl-4-[2-(2-phenyloxazol-4-yl)ethoxy]phenyl}propionicacid

To a 15 mL round bottom flask were charged 0.10 g (0.17 mmol) of3-{2-cyclohexylcarbamoyloxymethyl-4-[2-(2-phenyloxazol-4-yl)ethoxy]phenyl}propionicacid ethyl ester dissolved in 2 mL of ethanol. Next this solution wastreated with 0.48 mL (0.96 mmol) of 2N NaOH and then heated to 55° C.for 2 h. The volatiles were removed in vacuo and this crude residue wastaken up in 20 mL of EtOAc and 10 mL brine and acidified with 1 mL of 5NHCl. The aqueous layer was discarded and the organic layer was driedover Na₂SO₄ and removed in vacuo. The crude residue was submitted formass-directed HPLC purification to give a white solid (0.058 g, 63%). MS(ES) m/e 537 (M+1).

The following compounds were also prepared by this procedure:

Example 51

-   2-{2-Isopropylcarbamoyloxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic    acid, MS (ES) m/e 497 (M+1).

Example 52

-   2-{2-Benzylcarbamoyloxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic    acid, MS (ES) m/e 545 (M+1).

Example 53

-   2-{2-(4-Fluorobenzylcarbamoyloxymethyl)-4-[9-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic    acid, MS (ES) m/e 563 (M+1).

Example 54 Procedure 3

The following example exemplifies the general procedure for the parallelsynthesis of analogs utilizing the DynaVac carousel. To a 50 mL glasstube with screw cap and nitrogen inlet were charged2-{2-bromomethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid ethyl ester (0.040 g, 0.080 mmol), and 0.012 mL (0.12 mmol) ofm-cresol dissolved in 1 mL of absolute ethanol, followed by the additionof powdered potassium carbonate (325 mesh) (0.022 g, 0.16 mmol). Themixture was heated to 80° C. for 4 h. MS analysis of the reactionindicated that2-methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-m-tolyloxymethylphenoxy}propionicacid ethyl ester, MS (ES) m/e 530 (M+1) had formed. Next 0.4 mL of 5NNaOH was added and the reaction was heated for 3 h at 55° C. The ethanolwas removed in vacuo and the residue was treated with 0.75 mL of 5N HCland 1 mL of MeCl₂ and poured into a 3 mL ChemElute column to remove theaqueous layer. The column was eluted with additional MeCl₂ until nothingUV active remained on the column. The solvent was removed in vacuo. Thecrude residue was purified by mass-directed reverse phase HPLC toprovide 0.032 g (38%) of2-{2-bromomethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionicacid, MS (ES) m/e 502 (M+1).The following compounds were also prepared by this procedure:

Example 55

-   2-{2-(4-Fluorophenoxymethyl)-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic    acid, MS (ES) m/e 506 (M+1).

Example 56

-   2-{2-(3-Fluorophenoxymethyl)-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic    acid, MS (ES) m/e 506 (M+1).

Example 57

-   2-{2-(2-Fluorophenoxymethyl)-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic    acid, MS (ES) m/e 506 (M+1).

Example 58

-   2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-p-tolyloxymethylphenoxy}propionic    acid, MS (ES) m/e 502 (M+1)

Example 59

-   2-Methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-o-tolyloxymethylphenoxy}propionic    acid, MS (ES) m/e 502 (M+1).

Example 60

-   2-{2-(4-Methoxyphenoxymethyl)-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic    acid, MS (ES) m/e 518 (M+1).

Example 61

-   2-Methyl-2-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(4-trifluoromethylphenoxymethyl)phenoxy]propionic    acid, MS (ES) m/e 556 (M+1).

Example 62

-   2-{2-(Biphenyl-2-yloxymethyl)-4-[2-(5-methyl-O-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic    acid, MS (ES) m/e 564 (M+1).

Example 63

-   2-{2-(Biphenyl-4-yloxymethyl)-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic    acid, MS (ES) m/e 564 (M+1).

Binding and Cotransfection Studies

The in vitro potency of compounds in modulating PPARα and PPARγreceptors were determined by the procedures detailed below.DNA-dependent binding (ABCD binding) was carried out using SPAtechnology with PPAR receptors. Tritium-labeled PPARα and PPARγ agonistswere used as radioligands for generating displacement curves and IC₅₀values with compounds of the invention. Cotransfection assays werecarried out in CV-1 cells. The reporter plasmid contained an acylCoAoxidase (AOX) PPRE and TK promoter upstream of the luciferase reportercDNA. Appropriate PPARs and RXRα were constitutively expressed usingplasmids containing the CMV promoter. For PPARα and PPARβ, interferenceby endogenous PPARγ in CV-1 cells was an issue. In order to eliminatesuch interference, a GAL4 chimeric system was used in which the DNAbinding domain of the transfected PPAR was replaced by that of GAL4, andthe GAL4 response element was utilized in place of the AOX PPRE.Cotransfection efficacy was determined relative to PPARα agonist andPPARγ agonist reference molecules. Efficacies were determined bycomputer fit to a concentration-response curve, or in some cases at asingle high concentration of agonist (10 μM). For binding orcotransfection studies with receptors other than PPARs, similar assayswere carried out using appropriate ligands, receptors, reporterconstructs, etc., for that particular receptor.

These studies were carried out to evaluate the ability of compounds ofthe invention to bind to and/or activate various nuclear transcriptionfactors, particularly huPPARα (“hu” indicates “human”) and huPPARγ.These studies provide in vitro data concerning efficacy and selectivityof compounds of the invention. Furthermore, binding and cotransfectiondata for compounds of the invention were compared with correspondingdata for marketed compounds that act on either huPPARα or huPPARγ.

Binding and cotransfection data for representative compounds of theinvention are compared with corresponding data for reference compoundsin Table II.

TABLE II huPPARα huPPARγ Example IC₅₀(nM) CTF Eff.(%) IC₅₀(nM) CTFEff.(%)  1 1677 72 2127 69  6 535 80 268 71  9A 75 82 180 60 12 31 68219 66 12A 233 74 102 170 13 25 73 420 109 21 401 78 627 85 24 624 73239 94 26 3277 35 1151 52 26A 79 75 102 74 27A 113 95 49 63 30A 189 8078 92 30C 259 67 148 63 30J 82 90 83 50 31F 30 70 10 51 32 50 82 42 8037 294 91 172 60 38 254 80 81 65 39C 49 96 14 91 39I 182 91 86 85 39N 65102 173 51 Trogli- 94,500 0 1180 80 tazone Feno- 68,000 16 125,000 0fibric acid

Evaluation of Triglyceride and Cholesterol Level in HuapoAI TransgenicMice

Five to six week old male mice, transgenic for human apoAI[C57B1/6-tgn(apoa1)1rub, Jackson Laboratory, Bar Harbor, Me.] werehoused five per cage (10″×20″×8″ with aspen chip bedding) with food(Purina 5001) and water available at all times. After an acclimationperiod of 2 weeks, animals were individually identified by ear notches,weighed, and assigned to groups based on body weight. Beginning thefollowing morning, mice were dosed daily by oral gavage for 7 days usinga 20 gauge, 1½″ curved disposable feeding needle (Popper & Sons).Treatments were test compounds (30 mg/kg), a positive control(fenofibrate, 100 mg/kg) or vehicle [1% carboxymethylcellulose(w/v)/0.25% Tween80 (w/v); 0.2 ml/mouse]. Prior to termination on day 7,mice were weighed and dosed. Three hours after dosing, animals wereanesthetized by inhalation of isoflurane (2-4%; Abbott Laboratories,Chicago, Ill.) and blood obtained via cardiac puncture (0.7-1.0 ml).Whole blood was transferred to serum separator tubes (Vacutainer SST),chilled on ice, and permitted to clot. Serum was obtained aftercentrifugation at 4° C. and frozen until analysis for triglycerides,total cholesterol, compound levels, and serum lipoprotein profile byfast protein liquid chromatography (FPLC) coupled to an inline detectionsystem. After sacrifice by cervical dislocation, the liver, heart andepididymal fat pads were excised and weighed.

The animals dosed with vehicle had average triglycerides values of 60-80mg/dl, which were reduced by the positive control fenofibrate (33-58mg/dl with a mean reduction of 37%). The animals dosed with vehicle hadaverage total serum cholesterol values of 140-180 mg/dl, which wereincreased by fenofibrate (190-280 mg/dl, with a mean elevation of 41%).Triglyceride serum levels for animals receiving compounds of theinvention are reported in Table III in mg/dl. When subject to FPLCanalysis, pooled sera from vehicle-treated hu apoAI transgenic mice hada high density lipoprotein cholesterol (HDLc) peak area which rangedfrom 47 v-sec to 62 v-sec. Fenofibrate increased the amount of HDLc(68-96 v-sec with a mean percent increase of 48%). Test compounds arereported in terms of percent increase in the area under the curve asindicated in Table IV.

TABLE III Example % Triglyceride Reduction  1 79.2  3 66  6 35.4  9A67.1 12 74.3 13 44.8 24 75 26 25.5 26A 35.9 27A 29.5 30A 51.8 30C 6.231A −6.4 31F 35.7 37 29.9 38 39 39C 37.2

TABLE IV Example % HDLc Increase  1 77  3 63  6 20  9A 118 12 180 12A 4713 133 21 9 24 61 26 19 26A 43 27A 52 30A 93 30C 31 30J 77 31A 98 31F 7932 20 37 94 38 86 39C 97 39I 11 39N 16

Evaluation of Glucose Levels in db/db Mice

Five week old male diabetic (db/db) mice [C57BlKs/j-m +/+ Lepr(db),Jackson Laboratory, Bar Harbor, Me.] or lean littermates (db+) werehoused 6 per cage (10″×20″×8″ with aspen chip bedding) with food (Purina5015) and water available at all times. After an acclimation period of 2weeks, animals were individually identified by ear notches, weighed, andbled via the tail vein for determination of initial glucose levels.Blood was collected (100 μl) from unfasted animals by wrapping eachmouse in a towel, cutting the tip of the tail with a scalpel, andmilking blood from the tail into a heparinized capillary tube (Fisher)balanced on the edge of the bench. Sample was discharged into aheparinized microtainer with gel separator (VWR) and retained on ice.Plasma was obtained after centrifugation at 4° C. and glucose measuredimmediately. Remaining plasma was frozen until the completion of theexperiment, when glucose and triglycerides were assayed in all samples.Animals were grouped based on initial glucose levels and body weights.Beginning the following morning, mice were dosed daily by oral gavagefor 7 days using a 20 gauge, 1½″ curved disposable feeding needle.Treatments were test compounds (30 mg/kg), a positive control agent (30mg/kg) or vehicle [1% carboxymethylcellulose (w/v)/0.25% Tween80 (w/v);0.3 ml/mouse). On day 7, mice were weighed and bled (tail vein) 3 hoursafter dosing. Twenty-four hours after the 7^(th) dose (i.e., day 8),animals were bled again (tail vein). Samples obtained from consciousanimals on days 0, 7 and 8 were assayed for glucose. After the 24 hourbleed, animals were weighed and dosed for the final time. Three hoursafter dosing on day 8, animals were anesthetized by inhalation ofisoflurane and blood obtained via cardiac puncture (0.5-0.7 ml). Wholeblood was transferred to serum separator tubes, chilled on ice andpermitted to clot. Serum was obtained after centrifugation at 4° C. andfrozen until analysis for compound levels. After sacrifice by cervicaldislocation, the liver, heart and epididymal fat pads were excised andweighed.

The animals dosed with vehicle had average triglycerides values of170-230 mg/dl, which were reduced by the positive PPARγ control (70-120mg/dl with a mean reduction of 50%). Male db/db mice were hyperglycemic(average glucose of 680-730 mg/dl on the 7^(th) day of treatment), whilelean animals had average glucose levels between 190-230 mg/dl. Treatmentwith the positive control agent reduced glucose significantly (350-550mg/dl with a mean decrease towards normalization of 56%). Test compoundsare reported in Table V in terms of glucose normalization (i.e., 100%normalization would be glucose levels in treated db/db mice which didnot differ from lean values.

Glucose was measured calorimetrically using commercially purchasedreagents (Sigma #315-500). According to the manufacturers, theprocedures were modified from published work (McGowan, M. W., Artiss, J.D., Strandbergh, D. R. & Zak, B. Clin Chem, 20:470-5 (1974) and Keston,A. Specific calorimetric enzymatic analytical reagents for glucose.Abstract of papers 129th Meeting ACS, 31C (1956).); and depend on therelease of a mole of hydrogen peroxide for each mole of analyte, coupledwith a color reaction first described by Trinder (Trinder, P.Determination of glucose in blood using glucose oxidase with analternative oxygen acceptor. Ann Clin Biochem, 6:24 (1969)). Theabsorbance of the dye produced is linearly related to the analyte in thesample. The assays were further modified in our laboratory for use in a96 well format. Standards (Sigma #339-11, Sigma #16-11, and Sigma#CC0534 for glucose, triglycerides and total cholesterol, respectively),quality control plasma (Sigma # A2034), and samples (2 or 5 μl/well)were measured in duplicate using 200 μl of reagent. An additionalaliquot of sample, pipetted to a third well and diluted in 200 μl water,provided a blank for each specimen. Plates were incubated at roomtemperature (18, 15, and 10 minutes for glucose, triglycerides and totalcholesterol, respectively) on a plate shaker (DPC Micormix 5) andabsorbance read at 500 nm (glucose and total cholesterol) or 540 nm(triglycerides) on a plate reader (Wallac Victor 1420). Sampleabsorbances were compared to a standard curve (100-800, 10-500, and100-400 mg/dl for glucose, triglycerides and total cholesterol,respectively). Values for the quality control sample were always withinthe expected range and the coefficient of variation for samples wasbelow 10%. All samples from an experiment were assayed at the same timeto minimize inter-assay variability.

Serum lipoproteins were separated and cholesterol quantitated with anin-line detection system. Sample was applied to a Superose® 6 HR 10/30size exclusion column (Amersham Pharmacia Biotech) and eluted withphosphate buffered saline-EDTA at 0.5 ml/min. Cholesterol reagent (RocheDiagnostics Chol/HP 704036) at 0.16 ml/min mixed with the columneffluent through a T-connection and the mixture passed through a 15m×0.5 mm id knitted tubing reactor immersed in a 37 C water bath. Thecolored product produced in the presence of cholesterol was monitored inthe flow stream at 505 nm and the analog voltage from the monitor wasconverted to a digital signal for collection and analysis. The change involtage corresponding to change in cholesterol concentration was plottedvs time and the area under the curve corresponding to the elution ofVLDL, LDL and HDL was calculated using Perkin Elmer Turbochromesoftware.

TABLE V Glucose Example Normalization %  1 38  6 65  9A 86 12 101 12A 5113 65 21 23 24 72 26 42 26A 77 27A 62 30A 76 30C 48 30J 58 31A 19 31F 7732 47 37 56 38 38 39C 62 39I 26 39N 37

EQUIVALENTS

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. (canceled)
 2. (canceled)
 3. (canceled)
 4. (canceled)
 5. (canceled) 6.(canceled)
 7. (canceled)
 8. (canceled)
 9. (canceled)
 10. (canceled) 11.A compound represented by the following structural formula:

and pharmaceutically acceptable salts, solvates and hydrates thereof,wherein: R1 is an unsubstituted or substituted group selected from aryl,heteroaryl, cycloalkyl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl orcycloalkyl-C1-C4 alkyl; R5 is H, C1-C4 alkyl or aminoalkyl; R6 are each,independently, H, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl,C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-C1-C4 alkyl, aryl-C1-C4 alkyl,or together with the phenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthy; R7 are each, independently, H, halo, C1-C6alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cycloalkyl-C₁-C₄alkyl, or aryl-C1-C4 alkyl; R8 is C1-C4 alkyl or C1-C4 haloalkyl; R9 isC1-C6 alkyl or C1-C6 haloalkyl; and R10 is C1-C10 alkyl, C1-C₁₀haloalkyl, or a substituted or unsubstituted benzyl.
 12. A compound ofclaim 11 wherein R1 is substituted or unsubstituted phenyl.
 13. Acompound of claim 11 wherein R1 is substituted or unsubstitutedcyclohexyl.
 14. A compound of claim 11 wherein R1 is substituted orunsubstituted 2-thienyl.
 15. A compound of claim 11 wherein R8 and R9are each methyl.
 16. A compound of claim 11 wherein each R6 is H.
 17. Acompound of claim 11 wherein each R7 is H.
 18. (canceled)
 19. (canceled)20. (canceled)
 21. (canceled)
 22. A pharmaceutical composition,comprising a pharmaceutically acceptable carrier and a compound of claim11, or a pharmaceutically acceptable salt, solvate or hydrate thereof.23. (canceled)
 24. (canceled)
 25. (canceled)
 26. A method of treatingdiabetes mellitus in a mammal, comprising the step of administering tothe mammal a therapeutically effective amount of a compound of claim 11,or a pharmaceutically acceptable salt, solvate or hydrate thereof. 27.(canceled)
 28. (canceled)
 29. (canceled)
 30. (canceled)
 31. (canceled)32. (canceled)
 33. (canceled)
 34. (canceled)
 35. (canceled) 36.(canceled)
 37. (canceled)
 38. (canceled)
 39. (canceled)
 40. (canceled)41. (canceled)
 42. (canceled)
 43. (canceled)
 44. (canceled) 45.(canceled)
 46. (canceled)
 47. (canceled)
 48. (canceled)
 49. (canceled)50. (canceled)
 51. (canceled)
 52. (canceled)
 53. (canceled)
 54. Acompound represented by the following structural formula:

and pharmaceutically acceptable salts, solvates and hydrates thereof,wherein: R1 is an unsubstituted or substituted group selected from aryl,heteroaryl, cycloalkyl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl orcycloalkyl-C1-C4 alkyl; R5 is H, C1-C4 alkyl or aminoalkyl; R6 are each,independently, H, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl,C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-C1-C4 alkyl, aryl-C1-C4 alkyl,or together with the phenyl to which they are bound form naphthyl or1,2,3,4-tetrahydronaphthy; R7 are each, independently, H, halo, C1-C6alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cycloalkyl-C1-C4alkyl, or aryl-C1-C4 alkyl or C1-C6alkoxybenzyl, C1-C6 alkoxyaryl or agroup of the formula

R8 is C1-C4 alkyl or C1-C4 haloalkyl; R9 is C1-C6 alkyl or C1-C6haloalkyl; R10 is C1-C10 alkyl, C1-C10 haloalkyl, or a substituted orunsubstituted benzyl; and R13 is selected from the group consisting ofbenzyl, substituted benzyl, aryl, substituted aryl, substituted C1-C6cycloalkyl, C1-C6 cycloalkyl and C1-C6 alkyl.
 55. A compound of claim 54wherein R13 is selected from the group consisting of is selected fromthe group consisting of benzyl, substituted benzyl, C1-C6 cycloalkyl,C1-C6 alkyl.
 56. (canceled)
 57. (canceled)
 58. (canceled)
 59. (canceled)